The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact

Abstract

Hydrocephalus (HC) is a heterogenous disease characterized by alterations in cerebrospinal fluid (CSF) dynamics that may cause increased intracranial pressure. HC is a component of a wide array of genetic syndromes as well as a secondary consequence of brain injury (intraventricular hemorrhage (IVH), infection, etc.) that can present across the age spectrum, highlighting the phenotypic heterogeneity of the disease. Surgical treatments include ventricular shunting and endoscopic third ventriculostomy with or without choroid plexus cauterization, both of which are prone to failure, and no effective pharmacologic treatments for HC have been developed. Thus, there is an urgent need to understand the genetic architecture and molecular pathogenesis of HC. Without this knowledge, the development of preventive, diagnostic, and therapeutic measures is impeded. However, the genetics of HC is extraordinarily complex, based on studies of varying size, scope, and rigor. This review serves to provide a comprehensive overview of genes, pathways, mechanisms, and global impact of genetics contributing to all etiologies of HC in humans.

Introduction

Hydrocephalus (HC) is characterized by aberrant cerebrospinal fluid (CSF) dynamics (with or without ventricular dilation) that can lead to increased intracranial pressure. When left untreated, HC may be fatal and cause severe impairment in neurodevelopment. While classical theories of CSF posited that CSF is produced predominantly in the lateral ventricles via the choroid plexus and flows through the foramina of Monroe, third ventricle, cerebral aqueduct, and the fourth ventricle where it is disseminated through the central canal of the spinal cord and the subarachnoid space to be reabsorbed by arachnoid granulations [1], this model is no longer considered dogmatic [2]. Anatomical disruption of CSF flow and/or CSF pulsatility may result in a buildup of CSF to be classified as obstructive or non-communicating HC. However, HC can be communicating (i.e., no obvious anatomical blockade of absorption or obstruction), the result from increased production of CSF in response to injury, impaired absorption from the subarachnoid space, or result from defects in cortical development. These insults, in turn, may lead to ventricular dilation, among other potential and highly debated pathophysiologic mechanisms. Importantly, the global burden of HC is high [3], with significant morbidity and mortality regardless of treatment [4]. However, the genetic and mechanistic basis of HC remains poorly understood, largely due to the genetic complexity and phenotypic heterogeneity of the disease as well as cost of large-scale human genetics studies.

HC is a component of a wide-array of genetic syndromes [5], a secondary consequence of brain injury (intraventricular hemorrhage (IVH), infection, etc.) [6, 7], and a component of many central nervous system congenital abnormalities (i.e., neural tube defects, Chiari malformation, etc.) with a number of comorbid phenotypes including epilepsy and autism, among others. HC is a highly polygenic disease [8–10], with genes of varying functions and mechanisms conferring risk to the disease. The current treatments for HC are surgical interventions such as insertion of a ventricular (-peritoneal, atrial, etc.) shunt or endoscopic third ventriculostomy (ETV), which may be combined with choroid plexus cauterization (CPC) [6, 11]. While many studies have evaluated the efficacy and cost of these procedures [12], long-term morbidity of HC remains high and both treatments are prone to failure [13, 14]. Furthermore, while clinical trials have attempted pharmacological strategies to treat HC [15], no pharmacological treatment has been successful. In addition, HC may present in adulthood as normal pressure hydrocephalus (NPH). A more sophisticated and detailed understanding the genetic architecture and molecular pathogenesis of HC may lead to development of targeted pharmacologic treatments.

While numerous studies have aimed to identify causative genetic mechanisms leading to HC, largely based on isolated human case studies and murine models [5], critical limitations include cost, patient/family recruitment, number of patients (small by population-genetics’ standards), individual variant validation (typically de novo mutations), and very important species differences between model-organisms and human disease. Proposed pathophysiological mechanisms of HC include impaired development of the neural stem cell niche [16–20], abnormal ciliated ependymal cells [21–23], disruption of the ventricular zone [24, 25], and primary alterations in CSF absorption and/or secretion [26–29]. However, our understanding of these mechanisms is derived from varied model systems, which do not always accurately recapitulate the genetic and pathophysiological basis of human HC. Furthermore, there is increasing evidence that germline genetic variation contributes to risk of HC [5, 8, 10, 30]; however, most cases of HC remain genetically undefined and clinical genetic testing is rarely performed.

Elucidation of the genetic architecture of both shared and etiology-specific forms of HC may uncover pathophysiological mechanisms and correlate genetic risk factors with clinical and surgical outcomes, with the potential to directly influence surgical counseling and clinical management. While many genes have been implicated in the pathogenesis of HC in humans, the study designs, approaches, and levels of evidence identifying and validating these genetic findings vary greatly. Uncovering the genetic basis of HC relies on many factors, but most importantly on the clinical phenotype in question because HC rarely occurs in isolation. Comorbid phenotypes (neural tube defects, primary structural brain disorders, epilepsy, cognitive delay, etc.), and antecedent injuries – IVH and/or infection (meningitis, intracranial abscess, and/or sepsis), alone and in concert, confound most classical approaches to understanding genetic disease. Advancing our understanding of HC genetics, therefore, will necessitate understanding the extent to which co-occurring phenotypes are present and integration of multiple molecular and genetic data. Furthermore, elucidation of human-specific molecular mechanisms necessitates study in human tissue representative of the diverse populations HC affects. Here we summarize genetic studies of HC in humans and offer suggestions for advancing the field forward.

Methods

Search criteria

The US National Library of Medicine PubMed database and the Online Mendelian Inheritance in Man (OMIM) were queried for English-language studies using Title/Abstract, MeSH headings, key words, and genetic descriptors relevant to genetic causes of HC and ventriculomegaly. The OMIM database was used as an additional adjunct database as well. Our search terms are included below. Duplicates identified across multiple databases were identified. We strictly adhered to PRISMA guidelines [31].

Our PubMed search syntax included the following: (HC[Title/Abstract]) OR (Ventriculomegaly[Title/Abstract]); ((HC[MeSH Major Topic]) OR (Ventriculomegaly[MeSH Major Topic])) AND ("mendelian" OR "de novo" OR "functional genomics" OR "whole exome sequencing" OR "whole-genome sequencing" OR "genotyping" OR "genotype" OR "microarray" OR "genome-wide association study" OR "genome wide association study" OR "GWAS" OR "transcriptome wide association study" OR "transcriptome-wide association study" OR "TWAS" OR "gene expression" OR "copy number variation" OR "insertion" OR "deletion" OR "mosaic" OR "mosaicism" OR "genetic variation" OR "consanguineous" OR "consanguinity" OR "autosomal recessive" OR "autosomal dominant" OR "x-linked recessive" OR "x-linked dominant" OR "inherited" OR "inheritance" OR "non-coding" OR "coding" OR "co-expression" OR "germline" OR "linkage" OR "linkage disequilibrium" OR "genetic counseling" OR "syndrome" OR "syndromic" OR "genetic testing" OR "aqueductal stenosis" OR "obstructive HC" OR "acquired HC" OR "congenital HC" OR "proteomics" OR "proteomic" OR "metabolomic" OR "metabolomics" OR "methylation" OR "mutation" OR "genetic deficiency" OR "gain of function" OR "gain-of-function" OR "loss of function" OR "loss-of-function" OR "molecular"[Title/Abstract]).

We next queried the Online Mendelian Inheritance in Man (OMIM) database [32] using the search terms: “HC” or “ventriculomegaly” to identify genetic disease of which HC is a component. The search returned 671 entries which were manually reviewed. Duplicates within the OMIM database were excluded (n = 95). The resulting search query resulted in 3,709 studies.

Inclusion and exclusion criteria

Records (n = 3,709) from the above search were initially evaluated via abstract and screened for exclusion criteria: (1) Records published before 1970; (2) no genetic data of any kind; (3) no HC diagnosis; or (4) animal subjects. A total of 2,652 studies were excluded. Full text screening of the remaining papers (n = 1,057) was then screened for inclusion criteria. The second round of screening was carried out by full text review (n = 1,057). The same exclusion criteria were applied, while inclusion criteria were implemented: (1) Records published after 1970; (2) pediatric cohort (0–18 years of age); (3) primary genetic analysis; (4) confirmed diagnosis of human HC; and (5) human subjects. The final records were assessed for eligibility and records unavailable in English were excluded (n = 2). The final studies included (n = 327) were then evaluated for the methodology and type of genetic analysis performed. The papers included in our study (n = 327) were then subject to secondary analyses to assess for (1) change in number of publications over time; (2) geographic and ethnic associations of HC; (3) size of study; (4) central nervous system and non-central nervous system phenotypic associations. Figures were created using BioRender.

Author affiliation and subject country of origin

Authors’ institutional affiliation was obtained via PubMed’s “Affiliations” tab within the respective research articles PubMed webpage. Authors were then cross-referenced via Google search to increase validity of institutional affiliation at the time the study was performed. Articles were individually queried for the country of origin of patients with HC. If not explicitly stated, it was assumed that the patients were from the same country as the senior author’s affiliation. The total number of cases were tallied and tabulated on a world map using OpenStreetMap.

Results

HC in humans can be caused by or is secondary to several factors including structural brain disorders, cilia abnormalities, brain tumors resulting in CSF obstruction requiring CSF diversion, neural tube defects, prematurity and germinal matrix fragility, neonatal systemic and CNS infections, intracranial hemorrhage, evolutionary selection pressures, and ‘genetic’ anomalies, classically thought as Mendelian disorders (Fig. 1). Thus, we conducted a systematic review of human genetic studies of HC to quantify and summarize the current state of genetic contributions to HC of various etiologies (Fig. 2). However, genetic susceptibility confers risk to all these preceding factors as well as to HC directly. Thus, understanding the pleiotropic effect of genes on both risk factors and development of HC is needed and requires highly detailed phenomics analysis [33]. Here, we summarize all genetic studies of human HC across the age spectrum, including discussion of animal models of HC only as corroborating findings of genes and pathways identified in humans where there is a reasonable degree of evolutionary conservation. We believe this is essential as regulation of CSF and brain development is highly divergent across evolution, necessitating clarification and specificity of how genetics plays a role in human disease. Categories are defined a priori based on either phenotypic, molecular, or known genetic classifications. While many forms of HC can reasonably be classified into multiple categories, we attempt to simplify the groupings below.

Hydrocephalus secondary to aqueductal stenosis (AS)

Human genetics studies of HC secondary to aqueductal stenosis (AS) are summarized in Table 1. Fifteen unique gene mutations on 11 chromosomes inherited in both X-linked and autosomal patterns underlying HC secondary to AS have been identified. These genes include protocadherin 9 (PCDH9), immunoglobulin superfamily containing leucine rich repeat 2 (ISLR2), ATPase Na + /K + transporting subunit alpha 3 (ATP1A3), L1 cell adhesion molecule (L1CAM), FA complementation group C (FAC), fibroblast growth factor receptor 3 (FGFR3), solute carrier family 12 member 6 (SLC12A6), crumbs cell polarity complex component 2 (CRB2), Bardet-Biedl syndrome 7 (BBS7), podocin gene (NPHS2), multiple PDZ domain crumbs cell polarity complex component (MPDZ), laminin subunit beta 1 (LAMB1), alpha glucosidase (GAA), A-Disintegrin and Metalloproteinase with Thrombospondin motifs like 2 (ADAMTSL2), collagen type IV alpha 2 chain (COL4A2). A duplication in the Xp22.33 region and deletions of the long arm of chromosome 9, 12q22-q23.1, mutation in SRY-box transcription factor 2 (SOX2) gene, and mutation in the solute carrier family 12-member 7 (SLC12A7) gene were also identified.

Understanding the function of these genes may confer a mechanistic and phenotypic understanding of HC secondary to AS. For example, some patients with AS will display abnormal brainstem development leading to near complete obliteration of the aqueduct, whereas other children may display relatively normal anatomy associated with a web obscuring CSF flow. Genetics factors contributing to AS include ATP1A3, which encodes an ATPase ion channel that has been associated with CNS development and ventricular dilatation when disrupted in zebrafish [34]. In addition, SLC12A6 codes for the ion transporter KCC3 (K-Cl co transporter) that has been associated with AS among other phenotypes including peripheral neuropathy and agenesis of the corpus callosum in mice [35]. These ion channels are localized to the choroid plexus and are involved in neural stem cell development [36]. ADAMTSL2, encoding a glycoprotein, has been shown to interact with fibrillin 1 to enhance transforming growth factor- β (TGFβ) and fibroblast function. Additionally, TGFβ has been implicated in skeletal dysplasia and developmental dysfunction [37]. Thus, it is evident that genes with varying functions may contribute to AS and the diverse co-occurring phenotypes observed in these patients.

X-linked hydrocephalus

Genes contributing to X-linked HC include apoptosis inducing factor mitochondria associated 1 (AIFM1), adaptor related protein complex 1 subunit sigma 2 (AP1S2), EBP cholestenol delta-isomerase (EBP), FA complementation group B (FANCB), histone deacetylase 6 (HDAC6), OFD1 centriole and centriolar satellite protein (OFD1), OTU deubiquitinase 5 (OTUD5), coiled-coil domain containing 22 (CCDC22), and porcupine O-acyltransferase (PORCN). Table 2 summarizes the genetic studies of X-linked HC in humans. AIFM1 is involved in regulation of apoptosis [38]. In addition, AP1S2 regulates endosomal protein trafficking and structural integrity [39]. HDAC6 has been shown to interact with Runx2, a transcription factor involved in osteoblast differentiation, and other HDACs exhibit high expression patterns in prehypertrophic chondrocytes, indicating their role in endochondral ossification and skeletal dysplasias [40]. OTUD5 mutations also impact transcriptional regulation with its inability to prevent HDAC degradation and maintain neural stem cell development [41]. OFD1 and PORCN mutations affect signaling pathways such as hedgehog signaling or wingless/integrated (Wnt) signaling [42, 43].

L1CAM associated hydrocephalus

Next, we discuss L1CAM associated HC, as this entity is well described and distinct phenotypically. Early linkage analysis studies of HC identified a mutation within the long arm of chromosome X, specifically Xq28. Further genomic analyses localized to a region between the gene loci of DXS52 and F8C, within which L1 cell adhesion molecule (L1CAM) resides. The genetic understanding of X-linked HC has primarily been linked to genetic alterations at the L1CAM locus. L1CAM duplications include the 3’ end of the open reading frame and exons 2–10. L1CAM insertions include exon 18 and the junction sequence between L1CAM and AVPR2. L1CAM deletions/microdeletions include exons 2, 5–8, 10, 11, 18, 19, 21–23, 26, intron 18, and whole gene deletion. L1CAM missense mutations include exons 1–16, 18, 20, 21, 24, 27, 28 and introns 2–4, 6–8, 10–15, 18, 21, 22, 24, and 26. L1CAM nonsense mutations include exons 1, 3, 8, 10–14, and 20–22. A silent mutation in Exon 8 of L1CAM has been associated with HC. A summary of all mutations across L1CAM can be found in Fig. 3 and Table 3. Mutations in L1CAM are also associated with MASA syndrome (characterized by mental retardation, aphasia, shuffling gait, and adducted thumb), and spastic paraplegia, highlighting the pleiotropic role of L1CAM in human disease.

Dandy walker malformation

Dandy Walker malformation is a cerebellar structural anomaly that can impede CSF flow but can also be related to primary brain developmental alterations and contribute to HC development. Missense mutations are found in forkhead box C1 (FOXC1), fukutin (FKTN), laminin subunit gamma 1 (LAMC1), sphingosine-1-phosphate phosphatase 2 (SGPP2), and exocyst complex component 3 like 2 (EXOC3L2). Nonsense mutations are found in FKTN, nidogen 1 (NID1), and potassium channel tetramerization domain containing 3 (KCTD3). SIL1 nucleotide exchange factor (SIL1) displayed a nonstop mutation and carnitine palmitoyltransferase 2 (CPT2) displayed a deletion-insertion variant. Additional mutations included Zic family member 2 (ZIC2) and Zic family member 5 (ZIC5). Deletions were found in lysine methyltransferase 2D (KMT2D), chromosome 2 (2q36.1), chromosome 3 (3q25.1), chromosome 6 (6p24.1, 6p25.3), chromosome 7 (7p21.3), chromosome 8 (8q21), chromosome 12 (12q24), chromosome 13 (13q32), and chromosome 16 (16q21). The deletion of 8p21 resulted in the downregulation of fibroblast growth factor 17 (FGF17). Duplications were found in chromosome 6 (6p25.3), chromosome 7 (7p21.3), and chromosome 12 (12q24). In addition, EXOC3L2 regulates vesicular trafficking at synapses and cell polarity; a mutation within this gene locus can impact normal brain development [44]. KCTD3 is also highly expressed in the brain and kidneys and regulates ion channels such as hyperpolarization activated cyclic nucleotide-gated channel 3 (HCN3) [45]. SIL1 is a glycoprotein that regulates protein trafficking into the ER and ATPase activity, suggesting a mutated implication in protein folding through development [46, 47]. A patient with a mutation in CPT2, an enzyme responsible for breaking down long chain fatty acids, suggests a role of metabolic enzymes in the genetic susceptibility of HC secondary to Dandy Walker malformation [48]. Thus, Dandy Walker malformation related HC may be caused by a wide variety of genes involved in many biological processes. These data are summarized in Table 4.

Ciliopathy

Genes involved in cilia function that are associated with HC are summarized in Table 5. Primary cilia dysfunction has been demonstrated to play a role in HC with numerous Mendelian ‘ciliopathies’ resulting in HC. Missense mutations were observed in Meckel-Gruber syndrome gene (MKS3), MKS transition zone complex subunit 1 (MKS1), intraflagellar transport 43 (IFT43), WD repeat domain 35 (IFT121), coiled-coil and C2 domain containing 2A (CC2D2A), transmembrane protein 216 (TMEM216), PKHD1 ciliary IPT domain containing fibrocystin/polyductin (PKHD1), intestinal cell kinase (ICK), exon 14 of KIAA0586, exons 4 and 13 of centrosomal protein 83 (CEP83), exons 6, 11, 12, 20, 23, 24, 28, 29, 32, and 36 of SET binding factor 2 (SBF2), exon 9 of zinc finger E-box binding homeobox 1 (ZEB1), and exon 5 of G protein subunit alpha i2 (GNAI2). Nonsense mutations were identified in CC2D2A, IFT121, forkhead box J1 (FOXJ1), exon 2 of KIAA0586, exon 3 of centrosomal protein 55 (CEP55), exons 3, 4, 7, and 13 of CEP83, and exon 11 of SBF2. Deletions and duplications resulting in frameshift mutations were found in CC2D2A, MKS3, MKS1, dynein axonemal intermediate chain 2 (DNAI2), IFT121, FOXJ1, exon 5 and 17 of CEP83, and exon 4 of ZEB1. Exon 2 was deleted in WD repeat-containing protein 16 (WDR16). Additional mutations were found in WD repeat domain 93 (WDR93). Loss of MKS3 and MKS1 are associated with ciliary shortening and dysfunction, suggesting a role in primary ciliary development. TMEM216 also contributes to ciliary development through apical polarization and formation and may result in Joubert, Meckel and related syndromes [49]. IFT43 and IFT121 maintain cilium organization and regulate intraflagellar transport in interaction with the IFT-A complex [50]. In addition, CEP83 also interacts with IFT proteins and guides vesicular docking ciliogenesis [51]. One patient was identified with a mutation in DNAI2, a component of the outer dynein arm complex (ODA), which is involved in cilia motility [52]. ZEB1, SBF2, and GNAI2 are involved in other signaling pathways previously identified in association with HC [53].

PI3K-Akt-mTOR

Genes involved in PI3K-Akt-mTOR cell signaling pathway underlying HC are summarized in Table 6. Missense mutations were identified in ring finger protein 125 (RNF125), HECT and RLD domain containing E3 ubiquitin protein ligase family member 1 (HERC1), AKT serine/threonine kinase 3 (AKT3), mechanistic target of rapamycin kinase (mTOR), phosphatase and tensin homolog (PTEN), cyclin D2 (CCND2), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (exon 18 and others), phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) (exon 13 and others), and platelet derived growth factor receptor beta (PDGFRB) (exon 12 and others). Deletions were observed in PIK3CA, and nonsense mutations were seen in PTEN [54]. Deletions in chromosome 1 (1q42.3-q44) resulted in the deletion of AKT serine/threonine kinase 3 (AKT3). Additional genetic mutations implicated in this pathway included those in tripartite motif containing 71 (TRIM71), SWI/SNF related matrix associated, actin dependent regulator of chromatin (SMARCC1), forkhead box J1 (FOXJ1), formin 2 (FMN2), patched 1 (PTCH1), and FXYD domain containing ion transport regulator 2 (FXYD2). Multiple genes within the PI3K-AKT-MTOR pathway highlight convergence on molecular mechanisms conferring risk to HC. Murine models have demonstrated the role of HERC1, which codes for an E3 ubiquitin ligase, to affect Purkinje cell physiology and mTOR activity [55]. TRIM71 and SMARCC1 are expressed within the ventricles and epithelium of mice brains (determined via in situ hybridization) suggesting that a mutation within this gene locus can affect this region may lead to HC [8]. Mutations in FOXJ1 and FMN2 have been shown to alter neuroepithelial integrity and lead to HC in mice [56, 57]. Mice harboring mutations in PTCH1 also display defects in ependymal cell integrity [58]. Thus, mutations within many genes converging on PI3K-Akt-mTOR signaling have been widely implicated in HC pathophysiology.

Vesicle regulation & cell adhesion

Table 7 details mutations in genes responsible for vesicle regulation and cell adhesion that contribute to the development of HC. Missense mutations were found in and glial fibrillary acidic protein (GFAP). Sorting nexin 10 (SNX10) displayed a nonsense mutation and clathrin heavy chain (CLTC) displayed a frameshift mutation. Additional mutations include ArfGAP with FG repeats 1 (RAB), multiple PDZ domain crumbs cell polarity complex component (MPDZ), beta 1,3-glucosyltransferase (B3GALTL), SEC24 homolog D, COPII coat complex component (SEC24D), and actin beta (ACTB).

GFAP is required for white-matter architectural development and myelination, perhaps accounting for the neurodevelopmental comorbidities frequently observed in patients with HC [59]. Mutations in the phosphoinositide binding domain of SNX10 alters endosomal integrity, suggesting a potential pathogenic mechanism in vesicular trafficking [60]. Additionally, mutations in this gene locus can disrupt interactions between sorting nexins and the V-ATPase complex further contributing to vesicle dysfunction and ciliopathy [61]. CLTC contributes to the development of the vesicular coat, and a mutation within this gene locus may disrupt vesicle stability [62]. Mutations in RAB27A are associated with Griscelli syndrome, characterized by albinism, hematological abnormalities, and organ malformation which can also present with HC [63]. SEC24 is also involved in intracellular trafficking by interacting with export signals from the endoplasmic reticulum and regulating cargo transport [64]. In addition, MPDZ is highly expressed in tight junctions suggesting that a mutation within this gene locus may disrupt alter tissue permeability [65]. Finally, B3GALTL interacts with the thrombospondin type 1 repeat (TSR) protein family which play varied roles in maintain and regulating cell–cell adhesion [66].

Glycosylation defects

Table 8 summarizes genes implicated in human HC associated with defects in glycosylation. Nonsense mutations were seen in protein O-mannose kinase (POMK), and protein O-mannosyltransferase 1 (POMT1). Loss of function mutations were identified in dystroglycan 1 (DAG1) and isoprenoid synthase domain containing gene (ISPD). Additional mutations included those in protein C, inactivator of coagulation factors Va and VIIIa (PROC), fukutin related protein (FKRP), protein O-mannosyltransferase 2 (POMT2), protein O-linked mannose N-acetylglucosaminyltransferase 1 (beta 1,2-) (POMGNT1), LARGE xylosyl and glucuronyltransferase 1 (LARGE1) and a translocation between chromosome 5 and 6, t(5;6) (q35;q21). In addition, DAG1 codes for dystroglycan, a protein involved in extracellular matrix integrity and the genetic etiology of many neurological syndromes. Mutations in DAG1 have been found to contribute to Walker-Warburg syndrome and other muscular dystrophy-dystroglycanopathies which can be associated with HC [67]. Dystroglycan may also be affected through defects in its glycosylation patterns. For instance, mutations in POMK have been shown to impair the glycosylation of a-dystroglycan affecting cytoskeleton stability [68]. Other genes contributing to dystroglycanopathies through glycosylation errors include POMT1, POMT2, POMGNT1, FKRP, ISPD and LARGE1 [69].

Growth factor related signaling

Table 9 summarizes genetic mutations associated with growth factor related signaling dysfunction. Mutations were observed in fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), ZPR1 zinc finger (ZPR1), and fibrillin 1 (FBN1). Specifically, exon 7 displayed a missense mutation in FGFR2 and exon 64 displayed a mutation in FBN1. Mutations in FGFR play pleiotropic roles in numerous syndromes including Crouzon syndrome, Jackson-Weiss syndrome, Apert syndrome and Pfeiffer syndrome [70–73]. These craniosynostoses have been associated with HC and FGFR mutations contributing to bony abnormalities, which may explain the venous and CSF outflow obstructions leading to this phenotype [74]. The FGFR mutations identified are predominantly gain of function mutations altering ligand binding and tyrosine kinase activity [75]. In addition, ZPR1 contributes to cell proliferation and FBN1 is associated with TGF beta signaling suggesting their mechanistic contributions to the HC phenotype seen in patients with these phenotypes [76].

Extracellular matrix defects

Table 10 highlights the genetic mutations contributing to extracellular matrix defects. Mutations were found in fukutin (FKTN), cartilage associated protein (CRTAP), collagen type VIII alpha 2 chain (COL8A2), collagen type III alpha 1 chain (COL3A1), collagen type IV alpha 1 chain (COL4A1), vascular cell adhesion molecule 1 (VCAM1), protein tyrosine phosphatase receptor type F (PTPRF), fibrillin 1 (FBN1), laminin subunit beta 1 (LAMB1), FRAS1 related extracellular matrix 1 (FREM1), and the plasminogen gene. CRTAP is involved in proline hydroxylation which ultimately contributes to collagen stability and functionality [77]. Mutations within the CRTAP gene locus can lead to Cole-Carpenter syndrome, which is associated with HC [77]. Other basement membrane proteins encoded by COL8A2, COL3A1, COL4A1, VCAM1, and PTPRF may alert the extracellular matrix and contribute to HC. For instance, a mutation in COL3A1 affects its triple helix stability leading to degradation and further defects in the basement membrane [78]. LAMB1 knockdown in zebrafish disrupted laminin integrity, a component of the basal lamina, leading to brain structural abnormalities [79], suggesting a potential pathogenic link to HC.

Neurogenesis and neural stem cell biology

Table 11 summaries gene mutations implicating neurogenesis. Mutations were identified in SRY-box transcription factor 9 (SOX9), solute carrier family 29 member 3 (SLC29A3), adhesion G protein-coupled receptor (ADGRG1), katanin interacting protein (KIAA0556), G protein signaling modulator 2 (GPSM2), tripartite motif containing 71 (TRIM71) [80], SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily c member 1 (SMARCC1) [81], patched 1 (PTCH1), FLVCR heme transporter 2 (FLVCR2), intestinal cell kinase (ICK), cystathionine beta-synthase (CBS), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), interleukin 4 induced 1 (IL4I1), scribble planar cell polarity protein (SCRIB1), protein tyrosine kinase 7 (PTK7), frizzled class receptor 1 (FZD1), VANGL planar cell polarity protein 2 (VANGL2), dishevelled segment polarity protein (DVL2), transcription elongation factor B polypeptide 3B (TCEB3B), phospholipase C delta 4 (PLCD4), Ras associated domain family member 4 (RASSF4), phenylalanyl-tRNA synthetase 2, mitochondrial (FARS2), tubulin beta 3 class III (TUBB3), and discs large MAGUK scaffold protein 5 (DLG5). Frameshift mutations were seen in WD repeat domain 81 (WDR81), kinase D interacting substrate 220 (KIDINS220). Deletions were seen in chromosome 6 (6q25.3 and 6p25), chromosome 13 (13q), chromosome 16 (16p12.2), and chromosome 22 (22q11.2). The 6p25 deletion resulted in the deletion of forkhead box C1 (FOXC1), forkhead box F2 (FOXF2), and forkhead box Q1 (FOXQ1).

The heterogeneity of neurogenesis-associated HC suggests that numerous genes involved in development may confer susceptibility to this phenotype. SOX9 knockdown in mice suggest a role in neural stem cell development and ependymal cell maintenance as a pathogenic mechanism that causes HC [82]. In addition, mutations in ADGRG1 have been shown to impact cerebral cortex development and neuronal migration via the perturbation of the RhoA pathway [83]. In addition, GPSM2 has been shown to alter neuroepithelial function through disruption of cellular orientation and planarity leading to aberrant brain development [84]. Finally, mice lacking KIDINS220 display attenuated responses to neurotrophic factors and have impaired development in multiple signaling pathways [85]. Understanding the genetic influence of neurogenesis may elucidate a better understanding of patient characteristics and poor outcomes in the HC phenotype [86–89].

Inherited cancer syndromes

Table 12 summarizes genes that contributed to tumor pathogenesis, and which result in the development of HC. Mutations are seen in NRAS proto-oncogene, GTPase (NRAS), von Hippel-Lindau tumor suppressor (VHL), patched 1 (PTCH1) and FA complementation group C (FANCC). Germline mutations are seen in phosphatase and tensin homolog (PTEN) and SUFU negative regulator of hedgehog signaling (SUFU). Deletions within chromosome 11 (11p13) and chromosome 9 (9q22.3 and 9q22-q31) were also identified. NRAS is an oncogene contributing to the development of congenital melanocytic nevi, a condition associated with HC [90]. Clinically relevant mutations in Von Hippau Lindau (VHL) affect protein expression and degradation where patients with or without a mass lesion (i.e., hemangioblastoma) develop HC [91]. Gorlin syndrome is disorder characterized with bony abnormalities and an increased risk for multiple CNS and non-CNS tumors. Previous studies have mapped this syndrome to deletions in the 9q22 locus which is consistent with the patients identified in this review with mutations specifically affecting PTCH1 and FANCC genes [92, 93]. Finally, mutations in SUFU have also been associated with Gorlin syndrome [94, 95].

WNT signaling

WNT signal transduction is involved in numerous pathways regulating cell function and development. Table 13 summarizes gene mutations identified in HC patients with this pathway. Numerous studies have reported gene mutations in coiled-coil and C2 domain containing 2A (CC2D2A) and coiled-coil domain containing 88C (CCDC88C). COACH syndrome is defined as cerebellar vermis hypoplasia, oligophrenia, ataxia, colobomas, and hepatic fibrosis [96]. This gene locus has been shown to interact with the WNT signaling pathway and is associated with centrosome stability [97]. In addition, CCDC88C is associated with the WNT signaling pathway through interaction with the Dishevelled protein [98]. The dishevelled protein contains a binding domain which interacts with a hook related protein transcribed from the CCDC88C locus [99]. WNT signaling plays numerous roles in cell communication and embryonic development, suggesting potential mechanisms contributing to HC [100].

Transcriptional, post-transcriptional, and epigenetic regulation

Table 14 summarizes mutations in genes that regulate transcription, post-transcriptional, and epigenetic processes. Missense mutations were seen in THO complex subunit 6 (THOC6) and HYLS1, genes involved in transcriptional regulation. Patients with loss of function mutations in FA complementation group L (FANCL) we identified. Additional mutations observed included interferon regulatory factory 6 (IRF6), small nucleolar RNA, C/D box 118 (SNORD118), nuclear factor I A (NFIA), SET binding protein 1 (SETBP1), SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1 (SMARCB1), maelstrom spermatogenic transposon (MAEL), a deletion in chromosome 5 (5q35.3), and 20q13.3 trisomy. Deletions in chromosome 1 (1q42.3-q44) resulted in the deletion of zinc finger and BTB domain containing 18 (ZBTB18) and heterogeneous nuclear ribonucleoprotein U (HNRNPU). THOC6 is a part the TREX complex responsible for mRNA export and is localized to the 5’ cap of mRNA [101]. It has been associated with Beaulieu-Boycott-Innes syndrome, which is charactered by developmental delay and organ dysgenesis [102]. Patients identified in this review with Beaulieu-Boycott-Innes syndrome and THOC6 mutations have been shown to develop HC, suggesting a role for mRNA export regulation in association with HC phenotypes [103]. HYLS1 is associated with Hydrolethalus syndrome, a disorder characterized by HC and craniofacial abnormalities [104]. Expression analysis of this gene suggests a role in CNS development, where a HC associated mutation gene causes nuclear localization whereas the WT form is expressed in the cytoplasm [104]. SNORD118 is involved in regulation of ribosome biology and associated with the hydrocephalic phenotype of Labrune syndrome, characterized by leukoencephalopathy, intracranial cysts, and calcification [105]. While the function of SETBP1 remains largely unknown, mutations in this gene are associated with Schinzel-Giedion syndrome, characterized by facial abnormalities, intellectual disability, congenital malformations, and HC [106]. SMARCB1 is involved in chromatin remodeling to further enhance or repress transcription [107]. Finally, a transcriptome-wide association study (TWAS) and multi-omics study of HC identified maelstrom (MAEL), a gene that regulates transposons and epigenetic modifications, as an experiment-wide predictor of HC in the cortex [9, 108]. These studies identified transcriptional regulators and further emphasize the need to explore these mechanisms to understand the mechanistic associations with HC.

Ion transport and regulation

Table 15 summarizes gene mutations implicating ion transport. Mutations were seen in aquaporin 4 (AQP4) and FLVCR heme transporter 2 (FLVCR2). Mutations on chromosome 17 (17p13) implicated transient receptor potential cation channel subfamily V member 3 (TRPV3). Aquaporin 4 (AQP4) regulates water transport on ependymal cells and knockout of this gene in mice show disrupted gap junctions which alter the ependymal zone and CSF flow contributing to HC development [109; 110]. Mutations in the enhancer of TMEM50b alter expression of TTF, a direct transcriptional regulator of AQP1, have also been identified [101]. Mutations in FLVCR2 are associated with Fowler’s syndrome, a disorder characterized by HC and hydranencephaly [111]. This gene locus encodes a transmembrane protein involved in solute transport, suggesting that defects in chemiosmotic regulation contribute to HC development [112].

Normal pressure hydrocephalus

Normal pressure HC (NPH) is a form of communicating HC in which the progressive pressure of CSF is believed to result in in ventricular dilatation and further CSF accumulation. Table 16 summarizes the genes implicated in human studies of NPH. Scm like with four mbt domains 1 (SFMBT1) displayed an intron 2 deletion. Cilia and flagella associated protein 43 (CFAP43) was found to have a nonsense mutation. The gene locus contributing to the development of ETINPH, a disorder characterized with essential tremors and idiopathic NPH, was localized to 19q12-13.31 on chromosome 19. SFMBT1 is highly expressed in ependymal cells and epithelial cells of the brain, suggesting that a mutation in this gene locus may contribute to the dysfunctional CSF circulation [113]. Furthermore, a binding site had been identified within intron 2 of this gene locus, suggesting that the deletion of this intron, as seen in our review, will impact function [114; 115]. Deletion of cell wall biogenesis 43 (CWH43) in humans has also been associated with NPH [116].

Metabolism

Table 17 indicates genes involved in metabolic pathways. Mutations were seen in cytochrome c oxidase subunit 6B1 (COX6B1), methylenetetrahydrofolate reductase (MTHFR), and sulfatase modifying factor 1 (SUMF1). Mutations in COX6B1 have been shown to disrupt the electron transport chain suggesting that alterations in cellular energetics can contribute to HC [117] [118]. SUMF1 encodes formylglycine generating enzyme (FGE) involved in modifying cysteine residues in the endoplasmic reticulum [119]. MTHFR regulates folate metabolism, and mutations within this gene locus have been identified in congenital HC patients providing rationale to explore metabolic genes and their association with pathology [120].

Cell cycle and cytoarchitecture

Table 18 displays genes involved in cell cycle regulation and cytoarchitecture. Mutations were seen in spindle apparatus coiled-coil protein 1 (SPDL1), tubulin alpha 3e (TUBA3E), nidogen 1 (NID1), tRNA splicing endonuclease subunit 15 (TSEN15), clathrin heavy chain linker domain containing 1 (CLHC1), TBC1 domain containing kinase (TBCK), xin actin binding repeat containing 1 (XIRP1), nucleoporin 107 (NUP107), erythrocyte membrane protein band 4.1 like 4A (EPB41L4A), protein phosphatase 2 regulatory subunit B delta (PPP2R5D), protein phosphatase 2 scaffold subunit Alpha (PPP2R1A), prolyl 4-hydroxylase subunit beta (P4HB), and crumbs cell polarity complex component 2 (CRB2). SPDL1 has been shown to regulate mitotic checkpoints, and mutations arrested affected cells in metaphase [121]. TUBA3E maintains microtubule integrity by encoding for part of the microtubule heterodimer, alpha tubulin [122]. TSEN15 contributes to an endonuclease complex involved in tRNA splicing, and mutations affecting this gene locus can lead to defects in cell division [123]. XIRP1 has been shown to maintain actin integrity and stability [124]. P4HB encodes an enzyme subunit involved in collagen formation, and mutations affecting this gene location are associated with reduced cytoarchitectural stability [125].

Lipid structure and regulation

Table 19 summarizes genes involved in lipid structure and regulation associated with HC in humans. Mutations were seen in bridge-like lipid transfer protein family member 1 (KIAA1109), and glucosylceramidase beta 1 (GBA). The KIAA1109 ortholog in Drosophila melanogaster has shown to affect synaptic growth at the neuromuscular junction through modulation of phosphatidylinositol 4,5-bisphosphate (PIP²) [126]. GBA encodes for a lysosomal enzyme responsible for metabolizing glycolipids [127].

Genes of unknown function

Table 20 summarizes genes that are associated with HC pathology without a clear function. Additional variants include partial 1q trisomy, tetrasomy 5p, tetraploidy of chromosome 9, trisomy 9p, and chromosome 21 trisomy. Studies that have identified mutations in chromone 6 displayed microdeletions or mosaicism of monosomy. Deletions in chromosome 8 (8q12.2-q21.2) and chromosome 16 (16q) were also identified, and microduplications in chromosome 17 (17p13.1) have been reported. The vast genetic influence on HC emphasizes importance of exploring and understanding the factors that confer genetic risk to improve diagnostic and prognostic efficiency. Autosomal and sex chromosomal location of all genetic findings included in this review is summarized in Figs. 3, 4.

Global burden of genetic hydrocephalus

We next aimed to quantify the country of origin for patients included in this review (Fig. 5). Given the wide range of HC disease burden across the world [3], we aimed to determine if genetic studies of HC were similarly representative. What is clear is that for regions of the world where HC prevalence is highest (Africa, East Asia, etc.), there is an obvious lack of genetic studies of HC of any kind. For example, there is not a single study performed by authors in Sub-Saharan Africa (SSA) or including people from SSA. Given that African genomes are the most diverse and complex with generations of environmental pressures (including emerging pathogens) shaping the genome, understanding genetic risk factors in these populations is essential. While epidemiological estimates of the contribution of genetically linked forms of HC is not feasible at present, these data begin to highlight disparities in representation of genetic studies and the need for large-scale genetic studies of HC in diverse populations. These data also provide a reasonable estimate of the potential burden, although likely underestimated, contribution of genetic factors contributing to HC. It is our hope that this review highlights the diverse mechanisms underlying HC, the complex molecular pathways that may contribute to HC pathogenesis, and the need to greatly expand the representation of diverse peoples in HC genetics research.

Discussion

HC is a complex, heterogenous condition that can be a component of a wide range of genetic conditions and can be caused by a variety of preceding environmental factors. Because HC is a component of many syndromes with a wide range of concomitant phenotypes, understanding the genetic pleiotropism of contributing genes is important for delineating the pathophysiologic basis of the disease. This review provides a broad overview of the associations between genetic mechanisms underlying HC. The variability in phenotypes observed, methodology used to uncover genetic information, and wide range of validation of genetic findings highlights the major challenges in the field. While many studies are descriptive, a wide range of hypotheses are generated based on implicated genes and potential mechanisms. Specifically, many studies implicate alterations in neurogenesis and primary brain development, as opposed to direct alterations in CSF regulation, as potential pathophysiologic mechanisms. Overall, as genomic technologies become more ubiquitous in clinical practice and more patients undergo unbiased genomic sequencing, our understanding of HC will improve. However, there are several limitations and points to consider as this field evolves.

An ongoing challenge in human genetics is proving causality of implicated genetic findings. Classical validation technique requires reproducing the implicated mutation (if evolutionarily conserved) in a model organism such as a mouse or rat. However, the physiologic regulation of CSF and mechanisms underlying brain development are markedly different in these model organisms and often do not recapitulate human disease. Many genes underlying HC are associated with other phenotypes, and it may not be possible to identify a secondary causative genetic factor that unmasks the phenotype. Since this approach relies on the gene product being evolutionarily conserved, identification of human-specific disease mechanisms is impaired. Alternative approaches to determining the relationship of a gene variant to a HC phenotype include structural biologic modeling of presumed deleterious mutations; however, this approach does not consider physiological and phenotypic heterogeneity. Similarly, these approaches often rely on protein expression in prokaryotic systems, limiting interpretation of post-translational modifications and other physiologic contributors to protein function.

Based on the significant co-occurrence of traits affecting other organ systems, it is likely that genes associated with HC display significant pleiotropy. A simplistic model of monogenic contributions to HC is unlikely to capture the genetic etiology of most cases. Even among monogenic contributions to HC, there is significant phenotypic and genetic variability (i.e., L1CAM). As quantitative genetic methodology improves to identify polygenic contributors to disease, we suspect that a much larger proportion of cases will have polygenic contributions. Because HC is a heterogenous disease, accrual of large numbers of ‘homogenous’ cases are needed to accurately quantify reproductible genetic associations.

The variability in genomic technology used to determine potential genetic contributions to HC is significant. Agnostic methods such as genome wide association studies (GWAS), transcriptome-wide association studies (TWAS), whole-exome sequencing (WES), and whole-genome sequencing (WGS) have been used, but are limited by cost, sample size, and technical expertise involved in analysis. In contrast, targeted sequencing approaches rely on hypothesis-driven identification of implicated genetic loci introducing significant experimental bias.

Our review highlights that most genetic studies of HC are performed in countries where disease burden, paradoxically, is amongst the lowest in the world. This reflects disproportionately low resources for genetic studies in low- and middle-income countries. For example, Sub Saharan Africa the most genetically diverse and complex region in the world, where the burden of HC is also the highest, yet there are no genetic studies of HC of any kind in these populations. Although the burden of HC is largely the result of infections, the genetic contributors to infection susceptibility are largely uncharacterized in these populations. Evolutionary selection pressures have been differentially shaped by exposure to infectious pathogens, geographic shifts of ancestral peoples, and population isolation. Therefore, understanding genetic factors specific to these populations is paramount to improve secondary prevention and moving towards non-surgical treatment options.

Advances in genetic technology and interpretation coupled with decreased costs will garner a new era of precision medicine that can be applied in the clinic [128]. The extent to which genetic information may guide treatment in HC has not been fully realized. As more patients are rigorously studied using complementary and convergent genomic approaches coupled with long-term clinical outcomes, we may be able to incorporate genetic information into clinical care. Owing to the genetic architecture of HC highlighted here and across many studies, we anticipate that creation of polygenic risk scores (PRS) may be the most clinically meaningful and practical for disease prognostication and understanding comorbid disease risks.

Conclusions

HC is a phenotypically and genetically complex disease. While the literature describing the genetic causes of HC is vast, this comprehensive review highlights opportunities for further mechanistic study and disparities in ancestral representation. The varying rigor with which genetic studies are conducted highlights the challenge of determining causality of implicated genomic alterations, inadequacies of current model systems, and the need for human-specific molecular validation studies. What is clear is that our genetic understanding of HC is incomplete and our understanding of pleiotropy of implicated HC genes requires further maturation. This study represents the first large-scale systematic literature review of the genetic basis of HC in humans and highlights many areas ripe for future investigation.

Acknowledgements

AcknowledgementsNot applicable.

Competing interests

Competing interestsThe authors declare that the have no competing interests.

References

1. Khasawneh AH, Garling RJ, Harris CA. Cerebrospinal fluid circulation: what do we know and how do we know it?. Brain Circ. 2018 doi:10.4103/bc.BC_3_18 PubMed
2. Atchley TJ, Vukic B, Vukic M, Walters BC. Review of cerebrospinal fluid physiology and dynamics: a call for medical education reform. Neurosurgery. 2022 doi:10.1227/neu.0000000000002000 PubMed
3. Dewan MC, Rattani A, Mekary R, Glancz LJ, Yunusa I, Baticulon RE et al. Global hydrocephalus epidemiology and incidence: systematic review and meta-analysis. J Neurosurg. 2018 doi:10.3171/2017.10.JNS17439 PubMed
4. Gmeiner M, Wagner H, Zacherl C, Polanski P, Auer C, van Ouwerkerk WJ et al. Long-term mortality rates in pediatric hydrocephalus-a retrospective single-center study. Childs Nerv Syst. 2017 doi:10.1007/s00381-016-3268-y PubMed
5. Kousi M, Katsanis N. The Genetic Basis of Hydrocephalus. Annu Rev Neurosci. 2016 doi:10.1146/annurev-neuro-070815-014023 PubMed
6. Kahle KT, Kulkarni AV, Limbrick DD, Warf BC. Hydrocephalus in children. Lancet. 2016 doi:10.1016/S0140-6736(15)60694-8 PubMed
7. Tomycz LD, Hale AT, George TM. Emerging insights and new perspectives on the nature of hydrocephalus. Pediatr Neurosurg. 2017 doi:10.1159/000484173 PubMed
8. Furey CG, Choi J, Jin SC, Zeng X, Timberlake AT, Nelson-Williams C et al. De novo mutation in genes regulating neural stem cell fate in human congenital hydrocephalus. Neuron. 2018 doi:10.1016/j.neuron.2018.06.019 PubMed
9. Hale AT, Bastarache L, Morales DM, Wellons JC, Limbrick DD, Gamazon ER. Multi-omic analysis elucidates the genetic basis of hydrocephalus. Cell Rep. 2021 doi:10.1016/j.celrep.2021.109085 PubMed
10. Jin SC, Dong W, Kundishora AJ, Panchagnula S, Moreno-De-Luca A, Furey CG et al. Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus. Nat Med. 2020 doi:10.1038/s41591-020-1090-2 PubMed
11. Kulkarni AV, Schiff SJ, Mbabazi-Kabachelor E, Mugamba J, Ssenyonga P, Donnelly R et al. Endoscopic treatment versus shunting for infant hydrocephalus in Uganda. N Engl J Med. 2017 doi:10.1056/NEJMoa1707568 PubMed
12. J. Lim, A.R. Tang, C. Liles, A.A. Hysong, A.T. Hale, C.M. Bonfield, R.P. Naftel, J.C. Wellons, and C.N. Shannon, The cost of hydrocephalus: a cost-effectiveness model for evaluating surgical techniques. (2018) 1.10.3171/2018.6.PEDS1765430497214 doi:10.3171/2018.6.PEDS17654 PubMed
13. Hale AT, Riva-Cambrin J, Wellons JC, Jackson EM, Kestle JRW, Naftel RP et al. Machine learning predicts risk of cerebrospinal fluid shunt failure in children: a study from the hydrocephalus clinical research network. Childs Nerv Syst. 2021 doi:10.1007/s00381-021-05061-7 PubMed
14. Hale AT, Stanton AN, Zhao S, Haji F, Gannon SR, Arynchyna A et al. Predictors of endoscopic third ventriculostomy ostomy status in patients who experience failure of endoscopic third ventriculostomy with choroid plexus cauterization. J Neurosurg Pediatr. 2019 doi:10.3171/2019.2.PEDS18743 PubMed
15. Whitelaw A, Kennedy CR, Brion LP. Diuretic therapy for newborn infants with posthemorrhagic ventricular dilatation. Cochrane Database Syst Rev. 2001 doi:10.1002/14651858.CD002270 PubMed
16. C.G. Furey, J. Choi, S.C. Jin, X. Zeng, A.T. Timberlake, C. Nelson-Williams, M.S. Mansuri, Q. Lu, D. Duran, S. Panchagnula, A. Allocco, J.K. Karimy, A. Khanna, J.R. Gaillard, T. DeSpenza, P. Antwi, E. Loring, W.E. Butler, E.R. Smith, B.C. Warf, J.M. Strahle, D.D. Limbrick, P.B. Storm, G. Heuer, E.M. Jackson, B.J. Iskandar, J.M. Johnston, I. Tikhonova, C. Castaldi, F. Lopez-Giraldez, R.D. Bjornson, J.R. Knight, K. Bilguvar, S. Mane, S.L. Alper, S. Haider, B. Guclu, Y. Bayri, Y. Sahin, M.L.J. Apuzzo, C.C. Duncan, M.L. DiLuna, M. Gunel, R.P. Lifton, and K.T. Kahle, De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus. Neuron (2018).10.1016/j.neuron.2018.06.019PMC783907529983323 doi:10.1016/j.neuron.2018.06.019 PubMed
17. Lehtinen MK, Bjornsson CS, Dymecki SM, Gilbertson RJ, Holtzman DM, Monuki ES. The choroid plexus and cerebrospinal fluid: emerging roles in development, disease, and therapy. J Neurosci. 2013 doi:10.1523/JNEUROSCI.3258-13.2013 PubMed
18. Lehtinen MK, Walsh CA. Neurogenesis at the brain-cerebrospinal fluid interface. Annu Rev Cell Dev Biol. 2011 doi:10.1146/annurev-cellbio-092910-154026 PubMed
19. Lehtinen MK, Zappaterra MW, Chen X, Yang YJ, Hill AD, Lun M et al. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron. 2011 doi:10.1016/j.neuron.2011.01.023 PubMed
20. Carter CS, Vogel TW, Zhang Q, Seo S, Swiderski RE, Moninger TO et al. Abnormal development of NG2+PDGFR-alpha+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model. Nat Med. 2012 doi:10.1038/nm.2996 PubMed
21. Takagishi M, Sawada M, Ohata S, Asai N, Enomoto A, Takahashi K et al. Daple coordinates planar polarized microtubule dynamics in ependymal cells and contributes to hydrocephalus. Cell Rep. 2017 doi:10.1016/j.celrep.2017.06.089 PubMed
22. Wilson GR, Wang HX, Egan GF, Robinson PJ, Delatycki MB, O'Bryan MK et al. Deletion of the Parkin co-regulated gene causes defects in ependymal ciliary motility and hydrocephalus in the quakingviable mutant mouse. Hum Mol Genet. 2010 doi:10.1093/hmg/ddq031 PubMed
23. Wodarczyk C, Rowe I, Chiaravalli M, Pema M, Qian F, Boletta A. A novel mouse model reveals that polycystin-1 deficiency in ependyma and choroid plexus results in dysfunctional cilia and hydrocephalus. PLoS ONE. 2009 doi:10.1371/journal.pone.0007137 PubMed
24. Castaneyra-Ruiz L, Morales DM, McAllister JP, Brody SL, Isaacs AM, Strahle JM et al. Blood exposure causes ventricular zone disruption and glial activation in vitro. J Neuropathol Exp Neurol. 2018 doi:10.1093/jnen/nly058 PubMed
25. McAllister JP, Guerra MM, Ruiz LC, Jimenez AJ, Dominguez-Pinos D, Sival D et al. Ventricular zone disruption in human neonates with intraventricular hemorrhage. J Neuropathol Exp Neurol. 2017 doi:10.1093/jnen/nlx017 PubMed
26. Karimy JK, Zhang J, Kurland DB, Theriault BC, Duran D, Stokum JA et al. Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus. Nat Med. 2017 doi:10.1038/nm.4361 PubMed
27. Lun MP, Monuki ES, Lehtinen MK. Development and functions of the choroid plexus-cerebrospinal fluid system. Nat Rev Neurosci. 2015 doi:10.1038/nrn3921 PubMed
28. Robert SM, Reeves BC, Marlier A, Duy PQ, DeSpenza T, Kundishora A et al. Inflammatory hydrocephalus. Childs Nerv Syst. 2021 doi:10.1007/s00381-021-05255-z PubMed
29. Robert SM, Reeves BC, Kiziltug E, Duy PQ, Karimy JK, Mansuri MS et al. The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus. Cell. 2023 doi:10.1016/j.cell.2023.01.017 PubMed
30. Zhang J, Williams MA, Rigamonti D. Genetics of human hydrocephalus. J Neurol. 2006 doi:10.1007/s00415-006-0245-5 PubMed
31. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 doi:10.1136/bmj.n71 PubMed
32. Hamosh A, Scott AF, Amberger JS, Bocchini CA, McKusick VA. Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res. 2005 doi:10.1093/nar/gki033 PubMed
33. T.H. Andrew, Z. Dan, L.S. Rebecca, B. Lisa, W. Liuyang, S.Z. Sandra, J.S. Steven, C.K. Dennis, and R.G. Eric, The genetic architecture of human infectious diseases and pathogen-induced cellular phenotypes. medRxiv (2021) 2020.07.19.20157404.
34. Doğanli C, Beck HC, Ribera AB, Oxvig C, Lykke-Hartmann K. α3Na+/K+-ATPase deficiency causes brain ventricle dilation and abrupt embryonic motility in zebrafish. J Biol Chem. 2013 doi:10.1074/jbc.M112.421529 PubMed
35. Howard HC, Mount DB, Rochefort D, Byun N, Dupré N, Lu J et al. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet. 2002 doi:10.1038/ng1002 PubMed
36. Jin SC, Furey CG, Zeng X, Allocco A, Nelson-Williams C, Dong W et al. SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus. Mol Genet Genomic Med. 2019 doi:10.1002/mgg3.892 PubMed
37. Le Goff C, Morice-Picard F, Dagoneau N, Wang LW, Perrot C, Crow YJ et al. ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-β bioavailability regulation. Nat Genet. 2008 doi:10.1038/ng.199 PubMed
38. Berger I, Ben-Neriah Z, Dor-Wolman T, Shaag A, Saada A, Zenvirt S et al. Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing. Mol Genet Metab. 2011 doi:10.1016/j.ymgme.2011.09.020 PubMed
39. Saillour Y, Zanni G, Des-Portes V, Heron D, Guibaud L, Iba-Zizen MT et al. Mutations in the AP1S2 gene encoding the sigma 2 subunit of the adaptor protein 1 complex are associated with syndromic X-linked mental retardation with hydrocephalus and calcifications in basal ganglia. J Med Genetics. 2007 doi:10.1136/jmg.2007.051334 PubMed
40. Westendorf JJ, Zaidi SK, Cascino JE, Kahler R, van Wijnen AJ, Lian JB et al. Runx2 (Cbfa1, AML-3) interacts with histone deacetylase 6 and represses the p21(CIP1/WAF1) promoter. Mol Cell Biol. 2002 doi:10.1128/MCB.22.22.7982-7992.2002 PubMed
41. Beck DB, Basar MA, Asmar AJ, Thompson JJ, Oda H, Uehara DT et al. Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation. Sci Adv. 2021 doi:10.1126/sciadv.abe2116 PubMed
42. Peters T, Perrier R, Haber RM. Focal dermal hypoplasia: report of a case with myelomeningocele, Arnold-Chiari malformation and hydrocephalus with a review of neurologic manifestations of Goltz syndrome. Pediatr Dermatol. 2014 doi:10.1111/pde.12267 PubMed
43. Zhang YW, Qu HB, Long N, Leng XY, Liu YQ, Yang Y. A rare mutant of OFD1 gene responsible for Joubert syndrome with significant phenotype variation. Mol Genet Genomics. 2021 doi:10.1007/s00438-020-01726-1 PubMed
44. Grindstaff KK, Yeaman C, Anandasabapathy N, Hsu SC, Rodriguez-Boulan E, Scheller RH et al. Sec6/8 complex is recruited to cell-cell contacts and specifies transport vesicle delivery to the basal-lateral membrane in epithelial cells. Cell. 1998 doi:10.1016/S0092-8674(00)81435-X PubMed
45. Cao-Ehlker X, Zong X, Hammelmann V, Gruner C, Fenske S, Michalakis S et al. Up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) by specific interaction with K+ channel tetramerization domain-containing protein 3 (KCTD3). J Biol Chem. 2013 doi:10.1074/jbc.M112.434803 PubMed
46. Chung KT, Shen Y, Hendershot LM. BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP. J Biol Chem. 2002 doi:10.1074/jbc.M208377200 PubMed
47. Tyson JR, Stirling CJ. LHS1 and SIL1 provide a lumenal function that is essential for protein translocation into the endoplasmic reticulum. Embo J. 2000 doi:10.1093/emboj/19.23.6440 PubMed
48. Yahyaoui R, Espinosa MG, Gómez C, Dayaldasani A, Rueda I, Roldán A et al. Neonatal carnitine palmitoyltransferase II deficiency associated with Dandy-Walker syndrome and sudden death. Mol Genet Metab. 2011 doi:10.1016/j.ymgme.2011.05.003 PubMed
49. Valente EM, Logan CV, Mougou-Zerelli S, Lee JH, Silhavy JL, Brancati F et al. Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet. 2010 doi:10.1038/ng.594 PubMed
50. Duran I, Taylor SP, Zhang W, Martin J, Qureshi F, Jacques SM et al. Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia. Cilia. 2017 doi:10.1186/s13630-017-0051-y PubMed
51. Joo K, Kim CG, Lee M-S, Moon H-Y, Lee S-H, Kim MJ et al. CCDC41 is required for ciliary vesicle docking to the mother centriole. Proc Natl Acad Sci. 2013 doi:10.1073/pnas.1220927110 PubMed
52. Rocca MS, Piatti G, Michelucci A, Guazzo R, Bertini V, Vinanzi C et al. A novel genetic variant in DNAI2 detected by custom gene panel in a newborn with Primary Ciliary Dyskinesia: case report. BMC Med Genet. 2020 doi:10.1186/s12881-020-01160-5 PubMed
53. Mei H-F, Dong X-R, Chen H-Y, Lu Y-L, Wu B-B, Wang H-J et al. Genetic etiologies associated with infantile hydrocephalus in a Chinese infantile cohort. World J Pediatr. 2021 doi:10.1007/s12519-021-00429-w PubMed
54. DeSpenza T, Carlson M, Panchagnula S, Robert S, Duy PQ, Mermin-Bunnell N et al. PTEN mutations in autism spectrum disorder and congenital hydrocephalus: developmental pleiotropy and therapeutic targets. Trends Neurosci. 2021 doi:10.1016/j.tins.2021.08.007 PubMed
55. Mashimo T, Hadjebi O, Amair-Pinedo F, Tsurumi T, Langa F, Serikawa T et al. Progressive Purkinje cell degeneration in tambaleante mutant mice is a consequence of a missense mutation in HERC1 E3 ubiquitin ligase. PLoS Genet. 2009 doi:10.1371/journal.pgen.1000784 PubMed
56. Jacquet BV, Salinas-Mondragon R, Liang H, Therit B, Buie JD, Dykstra M et al. FoxJ1-dependent gene expression is required for differentiation of radial glia into ependymal cells and a subset of astrocytes in the postnatal brain. Development. 2009 doi:10.1242/dev.041129 PubMed
57. Lian G, Chenn A, Ekuta V, Kanaujia S, Sheen V. Formin 2 regulates lysosomal degradation of Wnt-associated β-catenin in neural progenitors. Cerebral Cortex. 2019 doi:10.1093/cercor/bhy073 PubMed
58. Gavino C, Richard S. Patched1 haploinsufficiency impairs ependymal cilia function of the quaking viable mice, leading to fatal hydrocephalus. Mol Cell Neurosci. 2011 doi:10.1016/j.mcn.2011.03.004 PubMed
59. Liedtke W, Edelmann W, Bieri PL, Chiu FC, Cowan NJ, Kucherlapati R et al. GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination. Neuron. 1996 doi:10.1016/S0896-6273(00)80194-4 PubMed
60. Qin B, He M, Chen X, Pei D. Sorting nexin 10 induces giant vacuoles in mammalian cells. J Biol Chem. 2006 doi:10.1074/jbc.M608884200 PubMed
61. Chen Y, Wu B, Xu L, Li H, Xia J, Yin W et al. A SNX10/V-ATPase pathway regulates ciliogenesis in vitro and in vivo. Cell Res. 2012 doi:10.1038/cr.2011.134 PubMed
62. DeMari J, Mroske C, Tang S, Nimeh J, Miller R, Lebel RR. CLTC as a clinically novel gene associated with multiple malformations and developmental delay. Am J Med Genet A. 2016 doi:10.1002/ajmg.a.37506 PubMed
63. Rajadhyax M, Neti G, Crow Y, Tyagi A. Neurological presentation of Griscelli syndrome: obstructive hydrocephalus without haematological abnormalities or organomegaly. Brain Develop. 2007 doi:10.1016/j.braindev.2006.09.007 PubMed
64. Miller EA, Schekman R. COPII—a flexible vesicle formation system. Curr Opin Cell Biol. 2013 doi:10.1016/j.ceb.2013.04.005 PubMed
65. Hamazaki Y, Itoh M, Sasaki H, Furuse M, Tsukita S. Multi-PDZ domain protein 1 (MUPP1) is concentrated at tight junctions through its possible interaction with claudin-1 and junctional adhesion molecule. J Biol Chem. 2002 doi:10.1074/jbc.M109005200 PubMed
66. Adams JC, Tucker RP. The thrombospondin type 1 repeat (TSR) superfamily: diverse proteins with related roles in neuronal development. Dev Dyn. 2000 doi:10.1002/(SICI)1097-0177(200006)218:2<280::AID-DVDY4>3.0.CO;2-0 PubMed
67. Michele DE, Barresi R, Kanagawa M, Saito F, Cohn RD, Satz JS et al. Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature. 2002 doi:10.1038/nature00837 PubMed
68. von Renesse A, Petkova MV, Lützkendorf S, Heinemeyer J, Gill E, Hübner C et al. POMK mutation in a family with congenital muscular dystrophy with merosin deficiency, hypomyelination, mild hearing deficit and intellectual disability. J Med Genet. 2014 doi:10.1136/jmedgenet-2013-102236 PubMed
69. Godfrey C, Clement E, Mein R, Brockington M, Smith J, Talim B et al. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain. 2007 doi:10.1093/brain/awm212 PubMed
70. Jabs EW, Li X, Scott AF, Meyers G, Chen W, Eccles M et al. Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2. Nat Genet. 1994 doi:10.1038/ng1194-275 PubMed
71. Lajeunie E, Ma HW, Bonaventure J, Munnich A, Le Merrer M, Renier D. FGFR2 mutations in Pfeiffer syndrome. Nat Genet. 1995 doi:10.1038/ng0295-108 PubMed
72. Reardon W, Winter RM, Rutland P, Pulleyn LJ, Jones BM, Malcolm S. Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet. 1994 doi:10.1038/ng0994-98 PubMed
73. Wilkie AO, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995 doi:10.1038/ng0295-165 PubMed
74. Rich PM, Cox TC, Hayward RD. The jugular foramen in complex and syndromic craniosynostosis and its relationship to raised intracranial pressure. AJNR Am J Neuroradiol. 2003 PubMed
75. Kan SH, Elanko N, Johnson D, Cornejo-Roldan L, Cook J, Reich EW et al. Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis. Am J Hum Genet. 2002 doi:10.1086/338758 PubMed
76. Ito YA, Smith AC, Kernohan KD, Pena IA, Ahmed A, McDonell LM et al. A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys. Clin Genet. 2018 doi:10.1111/cge.13388 PubMed
77. Balasubramanian M, Pollitt RC, Chandler KE, Mughal MZ, Parker MJ, Dalton A et al. CRTAP mutation in a patient with Cole-Carpenter syndrome. Am J Med Genet A. 2015 doi:10.1002/ajmg.a.36916 PubMed
78. Kroes HY, Pals G, van Essen AJ. Ehlers-Danlos syndrome type IV: unusual congenital anomalies in a mother and son with a COL3A1 mutation and a normal collagen III protein profile. Clin Genet. 2003 doi:10.1034/j.1399-0004.2003.00047.x PubMed
79. Lee J, Gross JM. Laminin beta1 and gamma1 containing laminins are essential for basement membrane integrity in the zebrafish eye. Invest Ophthalmol Vis Sci. 2007 doi:10.1167/iovs.06-1211 PubMed
80. Duy PQ, Weise SC, Marini C, Li XJ, Liang D, Dahl PJ et al. Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus. Nat Neurosci. 2022 doi:10.1038/s41593-022-01043-3 PubMed
81. A.K. Singh, G. Allington, S. Viviano, S. McGee, E. Kiziltug, S. Ma, S. Zhao, K.Y. Mekbib, J.P. Shohfi, P.Q. Duy, T. DeSpenza, Jr., C.G. Furey, B.C. Reeves, H. Smith, A.M.M. Sousa, A. Cherskov, A. Allocco, C. Nelson-Williams, S. Haider, S.R.A. Rizvi, S.L. Alper, N. Sestan, H. Shimelis, L.K. Walsh, R.P. Lifton, A. Moreno-De-Luca, S.C. Jin, P. Kruszka, E. Deniz, and K.T. Kahle, A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus. Brain (2023).10.1093/brain/awad405PMC1099453238128548 doi:10.1093/brain/awad405 PubMed
82. Scott CE, Wynn SL, Sesay A, Cruz C, Cheung M, Gomez-Gaviro MV et al. SOX9 induces and maintains neural stem cells. Nat Neurosci. 2010 doi:10.1038/nn.2646 PubMed
83. Luo R, Jeong SJ, Jin Z, Strokes N, Li S, Piao X. G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination. Proc Natl Acad Sci USA. 2011 doi:10.1073/pnas.1104821108 PubMed
84. Morin X, Jaouen F, Durbec P. Control of planar divisions by the G-protein regulator LGN maintains progenitors in the chick neuroepithelium. Nat Neurosci. 2007 doi:10.1038/nn1984 PubMed
85. Cesca F, Yabe A, Spencer-Dene B, Scholz-Starke J, Medrihan L, Maden CH et al. Kidins220/ARMS mediates the integration of the neurotrophin and VEGF pathways in the vascular and nervous systems. Cell Death Differ. 2012 doi:10.1038/cdd.2011.141 PubMed
86. Duy PQ, Rakic P, Alper SL, Robert SM, Kundishora AJ, Butler WE et al. A neural stem cell paradigm of pediatric hydrocephalus. Cerebral Cortex. 2023 doi:10.1093/cercor/bhac341 PubMed
87. Duy PQ, Rakic P, Alper SL, Butler WE, Walsh CA, Sestan N et al. Brain ventricles as windows into brain development and disease. Neuron. 2022 doi:10.1016/j.neuron.2021.12.009 PubMed
88. Duy PQ, Mehta NH, Kahle KT. The "microcephalic hydrocephalus" paradox as a paradigm of altered neural stem cell biology. Cerebral Cortex. 2024 doi:10.1093/cercor/bhad432 PubMed
89. Duy PQ, Kahle KT. "Floppy brain" in congenital hydrocephalus. Cerebral Cortex. 2023 doi:10.1093/cercor/bhad206 PubMed
90. Kinsler VA, Thomas AC, Ishida M, Bulstrode NW, Loughlin S, Hing S et al. Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS. J Invest Dermatol. 2013 doi:10.1038/jid.2013.70 PubMed
91. Jagannathan J, Lonser RR, Smith R, DeVroom HL, Oldfield EH. Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg. 2008 doi:10.3171/JNS/2008/108/2/0210 PubMed
92. Reichert SC, Zelley K, Nichols KE, Eberhard M, Zackai EH, Martinez-Poyer J. Diagnosis of 9q22.3 microdeletion syndrome in utero following identification of craniosynostosis, overgrowth, and skeletal anomalies. Am J Med Genet A. 2015 doi:10.1002/ajmg.a.37013 PubMed
93. Shimkets R, Gailani MR, Siu VM, Yang-Feng T, Pressman CL, Levanat S et al. Molecular analysis of chromosome 9q deletions in two Gorlin syndrome patients. Am J Hum Genet. 1996 PubMed
94. Pastorino L, Ghiorzo P, Nasti S, Battistuzzi L, Cusano R, Marzocchi C et al. Identification of a SUFU germline mutation in a family with Gorlin syndrome. Am J Med Genet A. 2009 doi:10.1002/ajmg.a.32944 PubMed
95. Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X et al. Mutations in SUFU predispose to medulloblastoma. Nat Genet. 2002 doi:10.1038/ng916 PubMed
96. Doherty D, Parisi MA, Finn LS, Gunay-Aygun M, Al-Mateen M, Bates D et al. Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). J Med Genet. 2010 doi:10.1136/jmg.2009.067249 PubMed
97. Gupta GD, Coyaud É, Gonçalves J, Mojarad BA, Liu Y, Wu Q et al. A dynamic protein interaction landscape of the human centrosome-cilium interface. Cell. 2015 doi:10.1016/j.cell.2015.10.065 PubMed
98. Ekici AB, Hilfinger D, Jatzwauk M, Thiel CT, Wenzel D, Lorenz I et al. Disturbed Wnt signalling due to a Mutation in CCDC88C causes an autosomal recessive non-syndromic hydrocephalus with medial diverticulum. Mol Syndromol. 2010 doi:10.1159/000319859 PubMed
99. Enomoto A, Ping J, Takahashi M. Girdin, a novel actin-binding protein, and its family of proteins possess versatile functions in the Akt and Wnt signaling pathways. Ann N Y Acad Sci. 2006 doi:10.1196/annals.1377.016 PubMed
100. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004 doi:10.1146/annurev.cellbio.20.010403.113126 PubMed
101. Cheng H, Dufu K, Lee CS, Hsu JL, Dias A, Reed R. Human mRNA export machinery recruited to the 5' end of mRNA. Cell. 2006 doi:10.1016/j.cell.2006.10.044 PubMed
102. Zhang Q, Chen S, Qin Z, Zheng H, Fan X. The first reported case of Beaulieu-Boycott-Innes syndrome caused by two novel mutations in THOC6 gene in a Chinese infant. Medicine (Baltimore). 2020 doi:10.1097/MD.0000000000019751 PubMed
103. Mattioli F, Isidor B, Abdul-Rahman O, Gunter A, Huang L, Kumar R et al. Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability. Hum Mol Genet. 2019 doi:10.1093/hmg/ddy391 PubMed
104. Mee L, Honkala H, Kopra O, Vesa J, Finnilä S, Visapää I et al. Hydrolethalus syndrome is caused by a missense mutation in a novel gene HYLS1. Hum Mol Genet. 2005 doi:10.1093/hmg/ddi157 PubMed
105. Jenkinson EM, Rodero MP, Kasher PR, Uggenti C, Oojageer A, Goosey LC et al. Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts. Nat Genet. 2016 doi:10.1038/ng.3661 PubMed
106. Hishimura N, Watari M, Ohata H, Fuseya N, Wakiguchi S, Tokutomi T et al. Genetic and prenatal findings in two Japanese patients with Schinzel-Giedion syndrome. Clin Case Rep. 2017 doi:10.1002/ccr3.738 PubMed
107. Wang X, Lee RS, Alver BH, Haswell JR, Wang S, Mieczkowski J et al. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nat Genet. 2017 doi:10.1038/ng.3746 PubMed
108. Sienski G, Dönertas D, Brennecke J. Transcriptional silencing of transposons by Piwi and maelstrom and its impact on chromatin state and gene expression. Cell. 2012 doi:10.1016/j.cell.2012.10.040 PubMed
109. Domínguez-Pinos MD, Páez P, Jiménez AJ, Weil B, Arráez MA, Pérez-Fígares JM et al. Ependymal denudation and alterations of the subventricular zone occur in human fetuses with a moderate communicating hydrocephalus. J Neuropathol Exp Neurol. 2005 doi:10.1097/01.jnen.0000171648.86718.bb PubMed
110. Li X, Kong H, Wu W, Xiao M, Sun X, Hu G. Aquaporin-4 maintains ependymal integrity in adult mice. Neuroscience. 2009 doi:10.1016/j.neuroscience.2009.04.044 PubMed
111. Meyer E, Ricketts C, Morgan NV, Morris MR, Pasha S, Tee LJ et al. Mutations in FLVCR2 are associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (Fowler syndrome). Am J Hum Genet. 2010 doi:10.1016/j.ajhg.2010.02.004 PubMed
112. Pao SS, Paulsen IT, Saier MH. Major facilitator superfamily. Microbiol Mol Biol Rev. 1998 doi:10.1128/MMBR.62.1.1-34.1998 PubMed
113. Kato T, Sato H, Emi M, Seino T, Arawaka S, Iseki C et al. Segmental copy number loss of SFMBT1 gene in elderly individuals with ventriculomegaly: a community-based study. Intern Med. 2011 doi:10.2169/internalmedicine.50.4505 PubMed
114. Kim JK, Huh SO, Choi H, Lee KS, Shin D, Lee C et al. Srg3, a mouse homolog of yeast SWI3, is essential for early embryogenesis and involved in brain development. Mol Cell Biol. 2001 doi:10.1128/MCB.21.22.7787-7795.2001 PubMed
115. Sato H, Takahashi Y, Kimihira L, Iseki C, Kato H, Suzuki Y et al. A segmental copy number loss of the SFMBT1 gene is a genetic risk for shunt-responsive, Idiopathic Normal Pressure Hydrocephalus (iNPH): a case-control study. PLoS ONE. 2016 doi:10.1371/journal.pone.0166615 PubMed
116. Yang HW, Lee S, Yang D, Dai H, Zhang Y, Han L et al. Deletions in CWH43 cause idiopathic normal pressure hydrocephalus. EMBO Mol Med. 2021 doi:10.15252/emmm.202013249 PubMed
117. Abdulhag UN, Soiferman D, Schueler-Furman O, Miller C, Shaag A, Elpeleg O et al. Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy. Eur J Human Genetics. 2015 doi:10.1038/ejhg.2014.85 PubMed
118. Sheftel AD, Wilbrecht C, Stehling O, Niggemeyer B, Elsässer HP, Mühlenhoff U et al. The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation. Mol Biol Cell. 2012 doi:10.1091/mbc.e11-09-0772 PubMed
119. Schlotawa L, Ennemann EC, Radhakrishnan K, Schmidt B, Chakrapani A, Christen HJ et al. SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency. Eur J Human Genetics. 2011 doi:10.1038/ejhg.2010.219 PubMed
120. Cizmeci MN, Akelma AZ, Kosehan D, Kutukoglu I, Sonmez FM. Multiloculated hydrocephalus of intrauterine-onset: a case report of an unexpected MTHFR A1298C positive test result. Genet Couns. 2013 PubMed
121. Barisic M, Sohm B, Mikolcevic P, Wandke C, Rauch V, Ringer T et al. Spindly/CCDC99 is required for efficient chromosome congression and mitotic checkpoint regulation. Mol Biol Cell. 2010 doi:10.1091/mbc.e09-04-0356 PubMed
122. Khodiyar VK, Maltais LJ, Ruef BJ, Sneddon KM, Smith JR, Shimoyama M et al. A revised nomenclature for the human and rodent alpha-tubulin gene family. Genomics. 2007 doi:10.1016/j.ygeno.2007.04.008 PubMed
123. Paushkin SV, Patel M, Furia BS, Peltz SW, Trotta CR. Identification of a human endonuclease complex reveals a link between tRNA splicing and pre-mRNA 3' end formation. Cell. 2004 doi:10.1016/S0092-8674(04)00342-3 PubMed
124. Pacholsky D, Vakeel P, Himmel M, Löwe T, Stradal T, Rottner K et al. Xin repeats define a novel actin-binding motif. J Cell Sci. 2004 doi:10.1242/jcs.01406 PubMed
125. Qi HH, Ongusaha PP, Myllyharju J, Cheng D, Pakkanen O, Shi Y et al. Prolyl 4-hydroxylation regulates Argonaute 2 stability. Nature. 2008 doi:10.1038/nature07186 PubMed
126. Khuong TM, Habets RL, Slabbaert JR, Verstreken P. WASP is activated by phosphatidylinositol-4,5-bisphosphate to restrict synapse growth in a pathway parallel to bone morphogenetic protein signaling. Proc Natl Acad Sci USA. 2010 doi:10.1073/pnas.1001794107 PubMed
127. Beutler E. Gaucher disease: new molecular approaches to diagnosis and treatment. Science. 1992 doi:10.1126/science.256.5058.794 PubMed
128. Sullivan W, Reeves BC, Duy PQ, Nelson-Williams C, Dong W, Jin SC et al. Exome sequencing as a potential diagnostic adjunct in sporadic congenital hydrocephalus. JAMA Pediatr. 2021 doi:10.1001/jamapediatrics.2020.4878 PubMed
129. Alazami AM, Maddirevula S, Seidahmed MZ, Albhlal LA, Alkuraya FS. A novel ISLR2-linked autosomal recessive syndrome of congenital hydrocephalus, arthrogryposis and abdominal distension. Hum Genet. 2019 doi:10.1007/s00439-018-1963-3 PubMed
130. Allocco AA, Jin SC, Duy PQ, Furey CG, Zeng X, Dong W et al. Recessive inheritance of congenital hydrocephalus with other structural brain abnormalities caused by compound heterozygous mutations in ATP1A3. Front Cell Neurosci. 2019 doi:10.3389/fncel.2019.00425 PubMed
131. Chassaing N, Gilbert-Dussardier B, Nicot F, Fermeaux V, Encha-Razavi F, Fiorenza M et al. Germinal mosaicism and familial recurrence of a SOX2 mutation with highly variable phenotypic expression extending from AEG syndrome to absence of ocular involvement. Am J Med Genet A. 2007 doi:10.1002/ajmg.a.31524 PubMed
132. Cox PM, Gibson RA, Morgan N, Brueton LA. VACTERL with hydrocephalus in twins due to Fanconi anemia (FA): mutation in the FAC gene. Am J Med Genet. 1997 doi:10.1002/(SICI)1096-8628(19970110)68:1<86::AID-AJMG17>3.0.CO;2-K PubMed
133. De Keersmaecker B, Van Esch H, Van Schoubroeck D, Claus F, Moerman P, De Catte L. Prenatal diagnosis of MPPH syndrome. Prenat Diagn. 2013 doi:10.1002/pd.4039 PubMed
134. Escobar LF, Hiett AK, Marnocha A. Significant phenotypic variability of Muenke syndrome in identical twins. Am J Med Genet A. 2009 doi:10.1002/ajmg.a.32841 PubMed
135. Gomy I, Heck B, Santos AC, Figueiredo MS, Martinelli CE, Nogueira MP et al. Two new Brazilian patients with Gómez-López-Hernández syndrome: reviewing the expanded phenotype with molecular insights. Am J Med Genet A. 2008 doi:10.1002/ajmg.a.32173 PubMed
136. Isik E, Onay H, Atik T, Akgun B, Cogulu O, Ozkinay F. Clinical and genetic features of L1 syndrome patients: Definition of two novel mutations. Clin Neurol Neurosurg. 2018 doi:10.1016/j.clineuro.2018.06.007 PubMed
137. Jin SC, Furey CG, Zeng X, Allocco A, Nelson-Williams C, Dong W et al. SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus. Mol Genet Genomic Med. 2019 doi:10.1002/mgg3.892 PubMed
138. Jouet M, Feldman E, Yates J, Donnai D, Paterson J, Siggers D et al. Refining the genetic location of the gene for X linked hydrocephalus within Xq28. J Med Genet. 1993 doi:10.1136/jmg.30.3.214 PubMed
139. Khattab M, Xu F, Li P, Bhandari V. A de novo 3.54 Mb deletion of 17q22-q23.1 associated with hydrocephalus: a case report and review of literature. Am J Med Genet A. 2011 doi:10.1002/ajmg.a.34307 PubMed
140. Lamont RE, Tan WH, Innes AM, Parboosingh JS, Schneidman-Duhovny D, Rajkovic A et al. Expansion of phenotype and genotypic data in CRB2-related syndrome. Eur J Human Genet. 2016 doi:10.1038/ejhg.2016.24 PubMed
141. Lyonnet S, Pelet A, Royer G, Delrieu O, Serville F, le Marec B et al. The gene for X-linked hydrocephalus maps to Xq28, distal to DXS52. Genomics. 1992 doi:10.1016/S0888-7543(05)80254-X PubMed
142. Maurya MR, Ravi R, Pungavkar SA. A case report of Arnold Chiari type 1 malformation in acromesomelic dwarf infant. Pan Afr Med J. 2021 doi:10.11604/pamj.2021.38.58.27295 PubMed
143. Porayette P, Fruitman D, Lauzon JL, Le Goff C, Cormier-Daire V, Sanders SP et al. Novel mutations in geleophysic dysplasia type 1. Pediatr Dev Pathol. 2014 doi:10.2350/13-08-1370-CR.1 PubMed
144. Serville F, Benit P, Saugier P, Vibert M, Royer G, Pelet A et al. Prenatal exclusion of X-linked hydrocephalus-stenosis of the aqueduct of Sylvius sequence using closely linked DNA markers. Prenat Diagn. 1993 doi:10.1002/pd.1970130603 PubMed
145. Strain L, Gosden CM, Brock DJ, Bonthron DT. Genetic heterogeneity in X-linked hydrocephalus: linkage to markers within Xq273. Am J Hum Genet. 1994 PubMed
146. Tzschach A, Grasshoff U, Schäferhoff K, Bonin M, Dufke A, Wolff M et al. Interstitial 9q34.11-q34.13 deletion in a patient with severe intellectual disability, hydrocephalus, and cleft lip/palate. Am J Med Genet A. 2012 doi:10.1002/ajmg.a.35398 PubMed
147. Verbeek E, Meuwissen ME, Verheijen FW, Govaert PP, Licht DJ, Kuo DS et al. COL4A2 mutation associated with familial porencephaly and small-vessel disease. Eur J Human Genet. 2012 doi:10.1038/ejhg.2012.20 PubMed
148. Vieira JP, Lopes P, Silva R. Primary ciliary dyskinesia and hydrocephalus with aqueductal stenosis. J Child Neurol. 2012 doi:10.1177/0883073811429856 PubMed
149. Alhousseini A, Zeineddine S, Husseini A, Baddah H, Saker H, Mody S et al. Familial Hydrocephalus and Dysgenesis of the Corpus Callosum Associated with Xp22.33 Duplication and Stenosis of the Aqueduct of Sylvius with X-Linked Recessive Inheritance Pattern. Gynecol Obstet Invest. 2019 doi:10.1159/000499505 PubMed
150. Beggs AH, Neumann PE, Arahata K, Arikawa E, Nonaka I, Anderson MS et al. Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy. Proc Natl Acad Sci USA. 1992 doi:10.1073/pnas.89.2.623 PubMed
151. Cacciagli P, Desvignes JP, Girard N, Delepine M, Zelenika D, Lathrop M et al. AP1S2 is mutated in X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome). Eur J Human Genet. 2014 doi:10.1038/ejhg.2013.135 PubMed
152. Chassaing N, Siani V, Carles D, Delezoide AL, Alberti EM, Battin J et al. X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia. Am J Med Genet A. 2005 doi:10.1002/ajmg.a.30570 PubMed
153. Furtado LV, Bayrak-Toydemir P, Hulinsky B, Damjanovich K, Carey JC, Rope AF. A novel X-linked multiple congenital anomaly syndrome associated with an EBP mutation. Am J Med Genet A. 2010 doi:10.1002/ajmg.a.33674 PubMed
154. Holden ST, Cox JJ, Kesterton I, Thomas NS, Carr C, Woods CG. Fanconi anaemia complementation group B presenting as X linked VACTERL with hydrocephalus syndrome. J Med Genet. 2006 doi:10.1136/jmg.2006.041673 PubMed
155. Jouet M, Moncla A, Paterson J, McKeown C, Fryer A, Carpenter N et al. New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome. Am J Hum Genet. 1995 PubMed
156. Kaepernick L, Legius E, Higgins J, Kapur S. Clinical aspects of the MASA syndrome in a large family, including expressing females. Clin Genet. 1994 doi:10.1111/j.1399-0004.1994.tb04019.x PubMed
157. Kenwrick S, Ionasescu V, Ionasescu G, Searby C, King A, Dubowitz M et al. Linkage studies of X-linked recessive spastic paraplegia using DNA probes. Hum Genet. 1986 doi:10.1007/BF00401241 PubMed
158. Ko TM, Hwa HL, Tseng LH, Hsieh FJ, Huang SF, Lee TY. Prenatal diagnosis of X-linked hydrocephalus in a Chinese family with four successive affected pregnancies. Prenat Diagn. 1994 doi:10.1002/pd.1970140110 PubMed
159. Kolanczyk M, Krawitz P, Hecht J, Hupalowska A, Miaczynska M, Marschner K et al. Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome. Eur J Human Genet. 2015 doi:10.1038/ejhg.2014.278 PubMed
160. Kroes HY, Nievelstein RJ, Barth PG, Nikkels PG, Bergmann C, Gooskens RH et al. Cerebral, cerebellar, and colobomatous anomalies in three related males: Sex-linked inheritance in a newly recognized syndrome with features overlapping with Joubert syndrome. Am J Med Genet A. 2005 doi:10.1002/ajmg.a.30690 PubMed
161. Legius E, Kaepernick L, Higgins JV, Glover TW. Fine mapping of X-linked clasped thumb and mental retardation (MASA syndrome) in Xq28. Clin Genet. 1994 doi:10.1111/j.1399-0004.1994.tb04016.x PubMed
162. McCauley J, Masand N, McGowan R, Rajagopalan S, Hunter A, Michaud JL et al. X-linked VACTERL with hydrocephalus syndrome: further delineation of the phenotype caused by FANCB mutations. Am J Med Genet A. 2011 doi:10.1002/ajmg.a.33913 PubMed
163. Mikat B, Roll C, Schindler D, Gembruch U, Klempert I, Buiting K et al. X-linked recessive VACTERL-H due to a mutation in FANCB in a preterm boy. Clin Dysmorphol. 2016 doi:10.1097/MCD.0000000000000111 PubMed
164. Rietschel M, Friedl W, Uhlhaas S, Neugebauer M, Heimann D, Zerres K. MASA syndrome: clinical variability and linkage analysis. Am J Med Genet. 1991 doi:10.1002/ajmg.1320410104 PubMed
165. Rosenthal A, Jouet M, Kenwrick S. Aberrant splicing of neural cell adhesion molecule L1 mRNA in a family with X-linked hydrocephalus. Nat Genet. 1992 doi:10.1038/ng1092-107 PubMed
166. Schrander-Stumpel C, Legius E, Fryns JP, Cassiman JJ. MASA syndrome: new clinical features and linkage analysis using DNA probes. J Med Genet. 1990 doi:10.1136/jmg.27.11.688 PubMed
167. Serville F, Lyonnet S, Pelet A, Reynaud M, Louail C, Munnich A et al. X-linked hydrocephalus: clinical heterogeneity at a single gene locus. Eur J Pediatr. 1992 doi:10.1007/BF01957757 PubMed
168. Sheen VL, Basel-Vanagaite L, Goodman JR, Scheffer IE, Bodell A, Ganesh VS et al. Etiological heterogeneity of familial periventricular heterotopia and hydrocephalus. Brain Develop. 2004 doi:10.1016/j.braindev.2003.09.004 PubMed
169. Simon D, Laloo B, Barillot M, Barnetche T, Blanchard C, Rooryck C et al. A mutation in the 3'-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia. Hum Mol Genet. 2010 doi:10.1093/hmg/ddq083 PubMed
170. Tripolszki K, Sasaki E, Hotakainen R, Kassim AH, Pereira C, Rolfs A et al. An X-linked syndrome with severe neurodevelopmental delay, hydrocephalus, and early lethality caused by a missense variation in the OTUD5 gene. Clin Genet. 2021 doi:10.1111/cge.13873 PubMed
171. Watanabe N, Tsutsumi S, Miyano Y, Sato H, Nagase S. X-linked VACTERL-H caused by deletion of exon 3 in FANCB: A case report. Congenit Anom (Kyoto). 2018 doi:10.1111/cga.12262 PubMed
172. Willems PJ, Dijkstra I, Van der Auwera BJ, Vits L, Coucke P, Raeymaekers P et al. Assignment of X-linked hydrocephalus to Xq28 by linkage analysis. Genomics. 1990 doi:10.1016/0888-7543(90)90294-5 PubMed
173. Willems PJ, Vits L, Raeymaekers P, Beuten J, Coucke P, Holden JJ et al. Further localization of X-linked hydrocephalus in the chromosomal region Xq28. Am J Hum Genet. 1992 PubMed
174. Bott L, Boute O, Mention K, Vinchon M, Boman F, Gottrand F. Congenital idiopathic intestinal pseudo-obstruction and hydrocephalus with stenosis of the aqueduct of sylvius. Am J Med Genet A. 2004 doi:10.1002/ajmg.a.30793 PubMed
175. Brewer CM, Fredericks BJ, Pont JM, Stephenson JB, Tolmie JL. X-linked hydrocephalus masquerading as spina bifida and destructive porencephaly in successive generations in one family. Dev Med Child Neurol. 1996 doi:10.1111/j.1469-8749.1996.tb12127.x PubMed
176. Chidsey BA, Baldwin EE, Toydemir R, Ahles L, Hanson H, Stevenson DA. L1CAM whole gene deletion in a child with L1 syndrome. Am J Med Genet A. 2014 doi:10.1002/ajmg.a.36474 PubMed
177. Claes S, Aguirre T, Simosa V, Bustos T, Lander R, Piras M et al. Hydrocephalus and spastic paraplegia result from a donor splice site mutation (2872 + 1G to A) in the L1CAM gene in a Venezuelan pedigree. Hum Mutat Suppl. 1998 doi:10.1002/humu.1380110177 PubMed
178. Coucke P, Vits L, Van Camp G, Serville F, Lyonnet S, Kenwrick S et al. Identification of a 5' splice site mutation in intron 4 of the L1CAM gene in an X-linked hydrocephalus family. Hum Mol Genet. 1994 doi:10.1093/hmg/3.4.671 PubMed
179. Du YZ, Dickerson C, Aylsworth AS, Schwartz CE. A silent mutation, C924T (G308G), in the L1CAM gene results in X linked hydrocephalus (HSAS). J Med Genet. 1998 doi:10.1136/jmg.35.6.456 PubMed
180. Du YZ, Srivastava AK, Schwartz CE. Multiple exon screening using restriction endonuclease fingerprinting (REF): detection of six novel mutations in the L1 cell adhesion molecule (L1CAM) gene. Hum Mutat. 1998 doi:10.1002/(SICI)1098-1004(1998)11:3<222::AID-HUMU7>3.0.CO;2-J PubMed
181. Du JS, Bason L, Woffendin H, Zackai E, Kenwrick S. Somatic and germ line mosaicism and mutation origin for a mutation in the L1 gene in a family with X-linked hydrocephalus. Am J Med Genet. 1998 doi:10.1002/(SICI)1096-8628(19980113)75:2<200::AID-AJMG16>3.0.CO;2-T PubMed
182. Ferese R, Zampatti S, Griguoli AM, Fornai F, Giardina E, Barrano G et al. A new splicing mutation in the L1CAM gene responsible for X-linked hydrocephalus (HSAS). J Mol Neurosci. 2016 doi:10.1007/s12031-016-0754-3 PubMed
183. Fernández RM, Núñez-Torres R, García-Díaz L, de Agustín JC, Antiñolo G, Borrego S. Association of X-linked hydrocephalus and Hirschsprung disease: report of a new patient with a mutation in the L1CAM gene. Am J Med Genet A. 2012 doi:10.1002/ajmg.a.35244 PubMed
184. Finckh U, Schröder J, Ressler B, Veske A, Gal A. Spectrum and detection rate of L1CAM mutations in isolated and familial cases with clinically suspected L1-disease. Am J Med Genet. 2000 doi:10.1002/(SICI)1096-8628(20000501)92:1<40::AID-AJMG7>3.0.CO;2-R PubMed
185. Fransen E, Schrander-Stumpel C, Vits L, Coucke P, Van Camp G, Willems PJ. X-linked hydrocephalus and MASA syndrome present in one family are due to a single missense mutation in exon 28 of the L1CAM gene. Hum Mol Genet. 1994 doi:10.1093/hmg/3.12.2255 PubMed
186. Gigarel N, Frydman N, Burlet P, Kerbrat V, Steffann J, Frydman R et al. Single cell co-amplification of polymorphic markers for the indirect preimplantation genetic diagnosis of hemophilia A, X-linked adrenoleukodystrophy, X-linked hydrocephalus and incontinentia pigmenti loci on Xq28. Hum Genet. 2004 doi:10.1007/s00439-003-1063-9 PubMed
187. Graf WD, Born DE, Shaw DW, Thomas JR, Holloway LW, Michaelis RC. Diffusion-weighted magnetic resonance imaging in boys with neural cell adhesion molecule L1 mutations and congenital hydrocephalus. Ann Neurol. 2000 doi:10.1002/1531-8249(200001)47:1<113::AID-ANA19>3.0.CO;2-P PubMed
188. Gregory LC, Shah P, Sanner JRF, Arancibia M, Hurst J, Jones WD et al. Mutations in MAGEL2 and L1CAM are associated with congenital hypopituitarism and arthrogryposis. J Clin Endocrinol Metab. 2019 doi:10.1210/jc.2019-00631 PubMed
189. Griseri P, Vos Y, Giorda R, Gimelli S, Beri S, Santamaria G et al. Complex pathogenesis of Hirschsprung's disease in a patient with hydrocephalus, vesico-ureteral reflux and a balanced translocation t(3;17)(p12;q11). Eur J Human Genet. 2009 doi:10.1038/ejhg.2008.191 PubMed
190. Gu SM, Orth U, Veske A, Enders H, Klunder K, Schlosser M et al. Five novel mutations in the L1CAM gene in families with X linked hydrocephalus. J Med Genet. 1996 doi:10.1136/jmg.33.2.103 PubMed
191. Guo D, Shi Y, Jian W, Fu Y, Yang H, Guo M et al. A novel nonsense mutation in the L1CAM gene responsible for X-linked congenital hydrocephalus. J Gene Med. 2020 doi:10.1002/jgm.3180 PubMed
192. Hübner CA, Utermann B, Tinschert S, Krüger G, Ressler B, Steglich C et al. Intronic mutations in the L1CAM gene may cause X-linked hydrocephalus by aberrant splicing. Hum Mutat. 2004 doi:10.1002/humu.9242 PubMed
193. Jouet M, Kenwrick S. Gene analysis of L1 neural cell adhesion molecule in prenatal diagnosis of hydrocephalus. Lancet. 1995 doi:10.1016/S0140-6736(95)90170-1 PubMed
194. Jouet M, Strain L, Bonthron D, Kenwrick S. Discordant segregation of Xq28 markers and a mutation in the L1 gene in a family with X linked hydrocephalus. J Med Genet. 1996 doi:10.1136/jmg.33.3.248 PubMed
195. Kanemura Y, Okamoto N, Sakamoto H, Shofuda T, Kamiguchi H, Yamasaki M. Molecular mechanisms and neuroimaging criteria for severe L1 syndrome with X-linked hydrocephalus. J Neurosurg. 2006 doi:10.3171/ped.2006.105.5.403 PubMed
196. Kong W, Wang X, Zhao J, Kang M, Xi N, Li S. A new frameshift mutation in L1CAM producing X-linked hydrocephalus. Mol Genet Genomic Med. 2020 doi:10.1002/mgg3.1031 PubMed
197. Liebau MC, Gal A, Superti-Furga A, Omran H, Pohl M. L1CAM mutation in a boy with hydrocephalus and duplex kidneys. Pediatr Nephrol. 2007 doi:10.1007/s00467-006-0424-8 PubMed
198. Limbrick DD, Baksh B, Morgan CD, Habiyaremye G, McAllister JP, Inder TE et al. Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus. PLoS ONE. 2017 doi:10.1371/journal.pone.0172353 PubMed
199. MacFarlane JR, Du JS, Pepys ME, Ramsden S, Donnai D, Charlton R et al. Nine novel L1 CAM mutations in families with X-linked hydrocephalus. Hum Mutat. 1997 doi:10.1002/(SICI)1098-1004(1997)9:6<512::AID-HUMU3>3.0.CO;2-3 PubMed
200. Marín R, Ley-Martos M, Gutiérrez G, Rodríguez-Sánchez F, Arroyo D, Mora-López F. Three cases with L1 syndrome and two novel mutations in the L1CAM gene. Eur J Pediatr. 2015 doi:10.1007/s00431-015-2560-2 PubMed
201. Marx M, Diestel S, Bozon M, Keglowich L, Drouot N, Bouché E et al. Pathomechanistic characterization of two exonic L1CAM variants located in trans in an obligate carrier of X-linked hydrocephalus. Neurogenetics. 2012 doi:10.1007/s10048-011-0307-4 PubMed
202. Michaelis RC, Du YZ, Schwartz CE. The site of a missense mutation in the extracellular Ig or FN domains of L1CAM influences infant mortality and the severity of X linked hydrocephalus. J Med Genet. 1998 doi:10.1136/jmg.35.11.901 PubMed
203. Nakakimura S, Sasaki F, Okada T, Arisue A, Cho K, Yoshino M et al. Hirschsprung's disease, acrocallosal syndrome, and congenital hydrocephalus: report of 2 patients and literature review. J Pediatr Surg. 2008 doi:10.1016/j.jpedsurg.2007.12.069 PubMed
204. Okamoto N, Wada Y, Goto M. Hydrocephalus and Hirschsprung's disease in a patient with a mutation of L1CAM. J Med Genet. 1997 doi:10.1136/jmg.34.8.670 PubMed
205. Okamoto N, Del Maestro R, Valero R, Monros E, Poo P, Kanemura Y et al. Hydrocephalus and Hirschsprung's disease with a mutation of L1CAM. J Hum Genet. 2004 doi:10.1007/s10038-004-0153-4 PubMed
206. Panayi M, Gokhale D, Mansour S, Elles R. Prenatal diagnosis in a family with X-linked hydrocephalus. Prenat Diagn. 2005 doi:10.1002/pd.1228 PubMed
207. Parisi MA, Kapur RP, Neilson I, Hofstra RM, Holloway LW, Michaelis RC et al. Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease?. Am J Med Genet. 2002 doi:10.1002/ajmg.10185 PubMed
208. Pomili G, Venti-Donti G, Alunni-Carrozza L, Ardisia C, Servidio F, Hofstra RM et al. MASA syndrome: ultrasonographic evidence in a male fetus. Prenat Diagn. 2000 doi:10.1002/1097-0223(200012)20:12<1012::AID-PD963>3.0.CO;2-X PubMed
209. Rehnberg M, Jonasson J, Gunnarsson C. Novel L1CAM splice site mutation in a young male with L1 syndrome. Am J Med Genet A. 2011 doi:10.1002/ajmg.a.33803 PubMed
210. G. Rodríguez-Criado, A. Pérez-Aytés, F. Martínez, Y.J. Vos, E. Verlind, A. González-Meneses López, I. Sánchez, and C. Schrander-Stumpel. X-linked hydrocephalus: another two families with an L1 mutation. Genet Couns 14 (2003) 57–65.12725590 PubMed
211. Ruiz JC, Cuppens H, Legius E, Fryns JP, Glover T, Marynen P et al. Mutations in L1-CAM in two families with X linked complicated spastic paraplegia, MASA syndrome, and HSAS. J Med Genet. 1995 doi:10.1136/jmg.32.7.549 PubMed
212. Saugier-Veber P, Martin C, Le Meur N, Lyonnet S, Munnich A, David A et al. Identification of novel L1CAM mutations using fluorescence-assisted mismatch analysis. Hum Mutat. 1998 doi:10.1002/(SICI)1098-1004(1998)12:4<259::AID-HUMU7>3.0.CO;2-A PubMed
213. Senat MV, Bernard JP, Delezoide A, Saugier-Veber P, Hillion Y, Roume J et al. Prenatal diagnosis of hydrocephalus-stenosis of the aqueduct of Sylvius by ultrasound in the first trimester of pregnancy Report of two cases. Prenat Diagn. 2001 doi:10.1002/pd.184 PubMed
214. Serikawa T, Nishiyama K, Tohyama J, Tazawa R, Goto K, Kuriyama Y et al. Prenatal molecular diagnosis of X-linked hydrocephalus via a silent C924T mutation in the L1CAM gene. Congenit Anom (Kyoto). 2014 doi:10.1111/cga.12069 PubMed
215. Silan F, Ozdemir I, Lissens W. A novel L1CAM mutation with L1 spectrum disorders. Prenat Diagn. 2005 doi:10.1002/pd.978 PubMed
216. Stowe RC, Lyons-Warren AM, Emrick L. Clinical Reasoning: Ventriculomegaly detected on 20-week anatomic fetal ultrasound. Neurology. 2018 doi:10.1212/WNL.0000000000006247 PubMed
217. Sztriha L, Frossard P, Hofstra RM, Verlind E, Nork M. Novel missense mutation in the L1 gene in a child with corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis, and hydrocephalus. J Child Neurol. 2000 doi:10.1177/088307380001500407 PubMed
218. Sztriha L, Vos YJ, Verlind E, Johansen J, Berg B. X-linked hydrocephalus: a novel missense mutation in the L1CAM gene. Pediatr Neurol. 2002 doi:10.1016/S0887-8994(02)00440-X PubMed
219. Takahashi S, Makita Y, Okamoto N, Miyamoto A, Oki J. L1CAM mutation in a Japanese family with X-linked hydrocephalus: a study for genetic counseling. Brain Develop. 1997 doi:10.1016/S0387-7604(97)00079-X PubMed
220. Takechi T, Tohyama J, Kurashige T, Maruta K, Uyemura K, Ohi T et al. A deletion of five nucleotides in the L1CAM gene in a Japanese family with X-linked hydrocephalus. Hum Genet. 1996 doi:10.1007/BF02185770 PubMed
221. Takenouchi T, Nakazawa M, Kanemura Y, Shimozato S, Yamasaki M, Takahashi T et al. Hydrocephalus with Hirschsprung disease: severe end of X-linked hydrocephalus spectrum. Am J Med Genet A. 2012 doi:10.1002/ajmg.a.35245 PubMed
222. Tegay DH, Lane AH, Roohi J, Hatchwell E. Contiguous gene deletion involving L1CAM and AVPR2 causes X-linked hydrocephalus with nephrogenic diabetes insipidus. Am J Med Genet A. 2007 doi:10.1002/ajmg.a.31536 PubMed
223. Van Camp G, Vits L, Coucke P, Lyonnet S, Schrander-Stumpel C, Darby J et al. A duplication in the L1CAM gene associated with X-linked hydrocephalus. Nat Genet. 1993 doi:10.1038/ng0893-421 PubMed
224. Verhagen WI, Bartels RH, Fransen E, van Camp G, Renier WO, Grotenhuis JA. Familial congenital hydrocephalus and aqueduct stenosis with probably autosomal dominant inheritance and variable expression. J Neurol Sci. 1998 doi:10.1016/S0022-510X(98)00097-5 PubMed
225. Vits L, Van Camp G, Coucke P, Fransen E, De Boulle K, Reyniers E et al. MASA syndrome is due to mutations in the neural cell adhesion gene L1CAM. Nat Genet. 1994 doi:10.1038/ng0794-408 PubMed
226. Vos YJ, de Walle HE, Bos KK, Stegeman JA, Ten Berge AM, Bruining M et al. Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis. J Med Genet. 2010 doi:10.1136/jmg.2009.071688 PubMed
227. Wilson PL, Kattman BB, Mulvihill JJ, Li S, Wilkins J, Wagner AF et al. Prenatal identification of a novel R937P L1CAM missense mutation. Genet Test Mol Biomarkers. 2009 doi:10.1089/gtmb.2009.0017 PubMed
228. Xie B, Luo J, Lei Y, Yang Q, Li M, Yi S et al. Two novel pathogenic variants of L1CAM gene in two fetuses with isolated X-linked hydrocephaly: a case report. Mol Med Rep. 2018 doi:10.3892/mmr.2018.9583 PubMed
229. Yamasaki M, Nonaka M, Suzumori N, Nakamura H, Fujita H, Namba A et al. Prenatal molecular diagnosis of a severe type of L1 syndrome (X-linked hydrocephalus). J Neurosurg Pediatr. 2011 doi:10.3171/2011.7.PEDS10531 PubMed
230. Aldinger KA, Lehmann OJ, Hudgins L, Chizhikov VV, Bassuk AG, Ades LC et al. FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation. Nat Genet. 2009 doi:10.1038/ng.422 PubMed
231. Arora V, Bijarnia-Mahay S, Kulshreshtra S, Singh K, Puri RD, Verma IC. Prenatal presentation of a rare genetic disorder: a clinical, autopsy and molecular correlation. Autops Case Rep. 2019 doi:10.4322/acr.2019.124 PubMed
232. Chen CP, Tzen CY, Chern SR, Tsai FJ, Hsu CY, Lee CC et al. A 12 Mb deletion of 6p24.1–>pter in an 18-gestational-week fetus with orofacial clefting, the Dandy-Walker malformation and bilateral multicystic kidneys. Eur J Med Genet. 2009 doi:10.1016/j.ejmg.2008.11.003 PubMed
233. Darbro BW, Mahajan VB, Gakhar L, Skeie JM, Campbell E, Wu S et al. Mutations in extracellular matrix genes NID1 and LAMC1 cause autosomal dominant Dandy-Walker malformation and occipital cephaloceles. Hum Mutat. 2013 doi:10.1002/humu.22351 PubMed
234. Faqeih EA, Almannai M, Saleh MM, AlWadei AH, Samman MM, Alkuraya FS. Phenotypic characterization of KCTD3-related developmental epileptic encephalopathy. Clin Genet. 2018 doi:10.1111/cge.13227 PubMed
235. Gai N, Jiang C, Zou YY, Zheng Y, Liang DS, Wu LQ. Novel SIL1 nonstop mutation in a Chinese consanguineous family with Marinesco-Sjögren syndrome and Dandy-Walker syndrome Clinica Chimica Acta. Int J Clin Chem. 2016 doi:10.1016/j.cca.2016.04.018 PubMed
236. Guo W, Zhao Y, Li S, Wang J, Liu X. Hypoglycemia and Dandy-Walker variant in a Kabuki syndrome patient: a case report. BMC Med Genet. 2020 doi:10.1186/s12881-020-01117-8 PubMed
237. Jalali A, Aldinger KA, Chary A, McLone DG, Bowman RM. Linkage to chromosome 2q361 in autosomal dominant Dandy-Walker malformation with occipital cephalocele and evidence for genetic heterogeneity. Hum Genet. 2008 doi:10.1007/s00439-008-0467-y PubMed
238. Liao C, Fu F, Li R, Yang X, Xu Q, Li DZ. Prenatal diagnosis and molecular characterization of a novel locus for Dandy-Walker malformation on chromosome 7p213. Eur J Med Genet. 2012 doi:10.1016/j.ejmg.2012.04.008 PubMed
239. Linpeng S, Liu J, Pan J, Cao Y, Teng Y, Liang D et al. Diagnosis of Joubert Syndrome 10 in a Fetus with Suspected Dandy-Walker Variant by WES: a novel splicing mutation in OFD1. Biomed Res Int. 2018 doi:10.1155/2018/4032543 PubMed
240. MacDonald EA, Holden JJ. Duplication 12q24––qter in an infant with Dandy-Walker syndrome. J Neurogenet. 1985 doi:10.3109/01677068509100147 PubMed
241. Mademont-Soler I, Morales C, Armengol L, Soler A, Sánchez A. Description of the smallest critical region for Dandy-Walker malformation in chromosome 13 in a girl with a cryptic deletion related to t(6;13)(q23;q32). Am J Med Genet A. 2010 doi:10.1002/ajmg.a.33550 PubMed
242. Matsukura H, Nagamori M, Miya K, Yorifuji T. MODY3, renal cysts, and Dandy-Walker variants with a microdeletion spanning the HNF1A gene. Clin Nephrol. 2017 doi:10.5414/CN109149 PubMed
243. Mimaki M, Shiihara T, Watanabe M, Hirakata K, Sakazume S, Ishiguro A et al. Holoprosencephaly with cerebellar vermis hypoplasia in 13q deletion syndrome: critical region for cerebellar dysgenesis within 13q322q34. Brain Dev. 2015 doi:10.1016/j.braindev.2014.10.009 PubMed
244. Shalata A, Lauhasurayotin S, Leibovitz Z, Li H, Hebert D, Dhanraj S et al. Biallelic mutations in EXOC3L2 cause a novel syndrome that affects the brain, kidney and blood. J Med Genet. 2019 doi:10.1136/jmedgenet-2018-105421 PubMed
245. Sudha T, Dawson AJ, Prasad AN, Konkin D, de Groot GW, Prasad C. De novo interstitial long arm deletion of chromosome 3 with facial dysmorphism, Dandy-Walker variant malformation and hydrocephalus. Clin Dysmorphol. 2001 doi:10.1097/00019605-200107000-00008 PubMed
246. Traversa A, Bernardo S, Paiardini A, Giovannetti A, Marchionni E, Genovesi ML et al. Prenatal whole exome sequencing detects a new homozygous fukutin (FKTN) mutation in a fetus with an ultrasound suspicion of familial Dandy-Walker malformation. Mol Genet Genomic Med. 2020 doi:10.1002/mgg3.1054 PubMed
247. Zaki MS, Masri A, Gregor A, Gleeson JG, Rosti RO. Dandy-Walker malformation, genitourinary abnormalities, and intellectual disability in two families. Am J Med Genet A. 2015 doi:10.1002/ajmg.a.37225 PubMed
248. Zanni G, Barresi S, Travaglini L, Bernardini L, Rizza T, Digilio MC et al. FGF17, a gene involved in cerebellar development, is downregulated in a patient with Dandy-Walker malformation carrying a de novo 8p deletion. Neurogenetics. 2011 doi:10.1007/s10048-011-0283-8 PubMed
249. Alby C, Piquand K, Huber C, Megarbané A, Ichkou A, Legendre M et al. Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome. Am J Hum Genet. 2015 doi:10.1016/j.ajhg.2015.06.003 PubMed
250. Al-Shroof M, Karnik AM, Karnik AA, Longshore J, Sliman NA, Khan FA. Ciliary dyskinesia associated with hydrocephalus and mental retardation in a Jordanian family. Mayo Clin Proc. 2001 doi:10.4065/76.12.1219 PubMed
251. Bachmann-Gagescu R, Ishak GE, Dempsey JC, Adkins J, O'Day D, Phelps IG et al. Genotype-phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures. J Med Genet. 2012 doi:10.1136/jmedgenet-2011-100552 PubMed
252. Bondeson ML, Ericson K, Gudmundsson S, Ameur A, Pontén F, Wesström J et al. A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy. Clin Genet. 2017 doi:10.1111/cge.13012 PubMed
253. Boycott KM, Parboosingh JS, Scott JN, McLeod DR, Greenberg CR, Fujiwara TM et al. Meckel syndrome in the Hutterite population is actually a Joubert-related cerebello-oculo-renal syndrome. Am J Med Genet A. 2007 doi:10.1002/ajmg.a.31832 PubMed
254. Dawe HR, Smith UM, Cullinane AR, Gerrelli D, Cox P, Badano JL et al. The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. Hum Mol Genet. 2007 doi:10.1093/hmg/ddl459 PubMed
255. Duran I, Taylor SP, Zhang W, Martin J, Qureshi F, Jacques SM et al. Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia. Cilia. 2017 doi:10.1186/s13630-017-0051-y PubMed
256. Edvardson S, Shaag A, Zenvirt S, Erlich Y, Hannon GJ, Shanske AL et al. Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation. Am J Hum Genet. 2010 doi:10.1016/j.ajhg.2009.12.007 PubMed
257. Failler M, Gee HY, Krug P, Joo K, Halbritter J, Belkacem L et al. Mutations of CEP83 cause infantile nephronophthisis and intellectual disability. Am J Hum Genet. 2014 doi:10.1016/j.ajhg.2014.05.002 PubMed
258. Kosaki K, Ikeda K, Miyakoshi K, Ueno M, Kosaki R, Takahashi D et al. Absent inner dynein arms in a fetus with familial hydrocephalus-situs abnormality. Am J Med Genet A. 2004 doi:10.1002/ajmg.a.30177 PubMed
259. Mei HF, Dong XR, Chen HY, Lu YL, Wu BB, Wang HJ et al. Genetic etiologies associated with infantile hydrocephalus in a Chinese infantile cohort. World J Pediatr. 2021 doi:10.1007/s12519-021-00429-w PubMed
260. Nabhan MM, Abdelaziz H, Xu Y, El Sayed R, Santibanez-Koref M, Soliman NA et al. Case report: whole-exome analysis of a child with polycystic kidney disease and ventriculomegaly. Genet Mol Res. 2015 doi:10.4238/2015.April.17.11 PubMed
261. Oud MM, Bonnard C, Mans DA, Altunoglu U, Tohari S, Ng AYJ et al. A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome. Cilia. 2016 doi:10.1186/s13630-016-0029-1 PubMed
262. Rocca MS, Piatti G, Michelucci A, Guazzo R, Bertini V, Vinanzi C et al. A novel genetic variant in DNAI2 detected by custom gene panel in a newborn with Primary Ciliary Dyskinesia: case report. BMC Med Genet. 2020 doi:10.1186/s12881-020-01160-5 PubMed
263. Wallmeier J, Frank D, Shoemark A, Nöthe-Menchen T, Cindric S, Olbrich H et al. De Novo Mutations in FOXJ1 result in a motile ciliopathy with hydrocephalus and randomization of left/right body asymmetry. Am J Hum Genet. 2019 doi:10.1016/j.ajhg.2019.09.022 PubMed
264. Cappuccio G, Ugga L, Parrini E, D'Amico A, Brunetti-Pierri N. Severe presentation and complex brain malformations in an individual carrying a CCND2 variant. Mol Genet Genomic Med. 2019 doi:10.1002/mgg3.708 PubMed
265. Maguolo A, Antoniazzi F, Spano A, Fiorini E, Gaudino R, Mauro M et al. Clinical pitfalls in the diagnosis of segmental overgrowth syndromes: a child with the c2740G > A mutation in PIK3CA gene. Ital J Pediatr. 2018 doi:10.1186/s13052-018-0568-8 PubMed
266. Maini I, Farnetti E, Caraffi SG, Ivanovski I, De Bernardi ML, Gelmini C et al. A Novel CCND2 mutation in a previously reported case of megalencephaly and perisylvian polymicrogyria with postaxial polydactyly and hydrocephalus. Neuropediatrics. 2018 doi:10.1055/s-0038-1641722 PubMed
267. McDermott JH, Hickson N, Banerjee I, Murray PG, Ram D, Metcalfe K et al. Hypoglycaemia represents a clinically significant manifestation of PIK3CA- and CCND2-associated segmental overgrowth. Clin Genet. 2018 doi:10.1111/cge.13145 PubMed
268. Mirzaa GM, Conti V, Timms AE, Smyser CD, Ahmed S, Carter M et al. Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study. The Lancet Neurol. 2015 doi:10.1016/S1474-4422(15)00278-1 PubMed
269. Mirzaa GM, Rivière JB, Dobyns WB. Megalencephaly syndromes and activating mutations in the PI3K-AKT pathway: MPPH and MCAP. Am J Med Genet C Semin Med Genet. 2013 doi:10.1002/ajmg.c.31361 PubMed
270. Ortega-Recalde O, Beltrán OI, Gálvez JM, Palma-Montero A, Restrepo CM, Mateus HE et al. Biallelic HERC1 mutations in a syndromic form of overgrowth and intellectual disability. Clin Genet. 2015 doi:10.1111/cge.12634 PubMed
271. Poduri A, Evrony GD, Cai X, Elhosary PC, Beroukhim R, Lehtinen MK et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron. 2012 doi:10.1016/j.neuron.2012.03.010 PubMed
272. Rivière JB, Mirzaa GM, O'Roak BJ, Beddaoui M, Alcantara D, Conway RL et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet. 2012 doi:10.1038/ng.2331 PubMed
273. Sameshima T, Morisada N, Egawa T, Kugo M, Iijima K. MPPH syndrome with aortic coarctation and macrosomia due to CCND2 mutations. Pediatr Int. 2020 doi:10.1111/ped.14068 PubMed
274. Szalai R, Melegh BI, Till A, Ripszam R, Csabi G, Acharya A et al. Maternal mosaicism underlies the inheritance of a rare germline AKT3 variant which is responsible for megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in two Roma half-siblings. Exp Mol Pathol. 2020 doi:10.1016/j.yexmp.2020.104471 PubMed
275. Tapper WJ, Foulds N, Cross NC, Aranaz P, Score J, Hidalgo-Curtis C et al. Megalencephaly syndromes: exome pipeline strategies for detecting low-level mosaic mutations. PLoS ONE. 2014 doi:10.1371/journal.pone.0086940 PubMed
276. Tenorio J, Mansilla A, Valencia M, Martínez-Glez V, Romanelli V, Arias P et al. A new overgrowth syndrome is due to mutations in RNF125. Hum Mutat. 2014 doi:10.1002/humu.22689 PubMed
277. Terrone G, Voisin N, Abdullah-Alfaiz A, Cappuccio G, Vitiello G, Guex N et al. De novo PIK3R2 variant causes polymicrogyria, corpus callosum hyperplasia and focal cortical dysplasia. Eur J Human Genet. 2016 doi:10.1038/ejhg.2016.7 PubMed
278. Zarate YA, Boccuto L, Srikanth S, Pauly R, Ocal E, Balmakund T et al. Constitutive activation of the PI3K-AKT pathway and cardiovascular abnormalities in an individual with Kosaki overgrowth syndrome. Am J Med Genet A. 2019 doi:10.1002/ajmg.a.61145 PubMed
279. Al-Dosari MS, Al-Owain M, Tulbah M, Kurdi W, Adly N, Al-Hemidan A et al. Mutation in MPDZ causes severe congenital hydrocephalus. J Med Genet. 2013 doi:10.1136/jmedgenet-2012-101294 PubMed
280. Al-Jezawi NK, Al-Shamsi AM, Suleiman J, Ben-Salem S, John A, Vijayan R et al. Compound heterozygous variants in the multiple PDZ domain protein (MPDZ) cause a case of mild non-progressive communicating hydrocephalus. BMC Med Genet. 2018 doi:10.1186/s12881-018-0540-x PubMed
281. Mégarbané A, Pangrazio A, Villa A, Chouery E, Maarawi J, Sabbagh S et al. Homozygous stop mutation in the SNX10 gene in a consanguineous Iraqi boy with osteopetrosis and corpus callosum hypoplasia. Eur J Med Genet. 2013 doi:10.1016/j.ejmg.2012.10.010 PubMed
282. Reis LM, Tyler RC, Abdul-Rahman O, Trapane P, Wallerstein R, Broome D et al. Mutation analysis of B3GALTL in Peters Plus syndrome. Am J Med Genet A. 2008 doi:10.1002/ajmg.a.32498 PubMed
283. Rodriguez D, Gauthier F, Bertini E, Bugiani M, Brenner M, N'Guyen S et al. Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation. Am J Hum Genet. 2001 doi:10.1086/323799 PubMed
284. Sakakibara T, Takahashi Y, Fukuda K, Inoue T, Kurosawa T, Nishikubo T et al. A case of infantile Alexander disease diagnosed by magnetic resonance imaging and genetic analysis. Brain Develop. 2007 doi:10.1016/j.braindev.2007.02.002 PubMed
285. Saugier-Veber P, Marguet F, Lecoquierre F, Adle-Biassette H, Guimiot F, Cipriani S et al. Hydrocephalus due to multiple ependymal malformations is caused by mutations in the MPDZ gene. Acta Neuropathol Commun. 2017 doi:10.1186/s40478-017-0438-4 PubMed
286. Takeyari S, Kubota T, Miyata K, Yamamoto K, Nakayama H, Yamamoto K et al. Japanese patient with Cole-carpenter syndrome with compound heterozygous variants of SEC24D. Am J Med Genet A. 2018 doi:10.1002/ajmg.a.40643 PubMed
287. van der Knaap MS, Salomons GS, Li R, Franzoni E, Gutiérrez-Solana LG, Smit LM et al. Unusual variants of Alexander's disease. Ann Neurol. 2005 doi:10.1002/ana.20381 PubMed
288. Zhang K, Cox E, Strom S, Xu ZL, Disilvestro A, Usrey K. Prenatal presentation and diagnosis of Baraitser-Winter syndrome using exome sequencing. Am J Med Genet A. 2020 doi:10.1002/ajmg.a.61725 PubMed
289. Beltran-Valero de Bernabé D, Voit T, Longman C, Steinbrecher A, Straub V, Yuva Y et al. Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome. J Med Genet. 2004 doi:10.1136/jmg.2003.013870 PubMed
290. Beltrán-Valero de Bernabé D, Currier S, Steinbrecher A, Celli J, van Beusekom E, van der Zwaag B et al. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet. 2002 doi:10.1086/342975 PubMed
291. Biancheri R, Bertini E, Falace A, Pedemonte M, Rossi A, D'Amico A et al. POMGnT1 mutations in congenital muscular dystrophy: genotype-phenotype correlation and expanded clinical spectrum. Arch Neurol. 2006 doi:10.1001/archneur.63.10.1491 PubMed
292. Bouchet C, Gonzales M, Vuillaumier-Barrot S, Devisme L, Lebizec C, Alanio E et al. Molecular heterogeneity in fetal forms of type II lissencephaly. Hum Mutat. 2007 doi:10.1002/humu.20561 PubMed
293. Cormand B, Pihko H, Bayés M, Valanne L, Santavuori P, Talim B et al. Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease. Neurology. 2001 doi:10.1212/WNL.56.8.1059 PubMed
294. Currier SC, Lee CK, Chang BS, Bodell AL, Pai GS, Job L et al. Mutations in POMT1 are found in a minority of patients with Walker-Warburg syndrome. Am J Med Genet A. 2005 doi:10.1002/ajmg.a.30487 PubMed
295. Geis T, Rödl T, Topaloğlu H, Balci-Hayta B, Hinreiner S, Müller-Felber W et al. Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders. Orphanet J Rare Dis. 2019 doi:10.1186/s13023-019-1119-0 PubMed
296. Hehr U, Uyanik G, Gross C, Walter MC, Bohring A, Cohen M et al. Novel POMGnT1 mutations define broader phenotypic spectrum of muscle-eye-brain disease. Neurogenetics. 2007 doi:10.1007/s10048-007-0096-y PubMed
297. Ichiyama M, Ohga S, Ochiai M, Fukushima K, Ishimura M, Torio M et al. Fetal hydrocephalus and neonatal stroke as the first presentation of protein C deficiency. Brain Develop. 2016 doi:10.1016/j.braindev.2015.07.004 PubMed
298. Kano H, Kobayashi K, Herrmann R, Tachikawa M, Manya H, Nishino I et al. Deficiency of alpha-dystroglycan in muscle-eye-brain disease. Biochem Biophys Res Commun. 2002 doi:10.1006/bbrc.2002.6608 PubMed
299. Karadeniz N, Zenciroğlu A, Gürer YK, Senbil N, Karadeniz Y, Topalŏlu H. De novo translocation t(5;6)(q35;q21) in an infant with Walker-Warburg syndrome. Am J Med Genet. 2002 doi:10.1002/ajmg.10286 PubMed
300. Preiksaitiene E, Voisin N, Gueneau L, Benušienė E, Krasovskaja N, Blažytė EM et al. Pathogenic homozygous variant in POMK gene is the cause of prenatally detected severe ventriculomegaly in two Lithuanian families. Am J Med Genet A. 2020 doi:10.1002/ajmg.a.61453 PubMed
301. van Reeuwijk J, Janssen M, van den Elzen C, Beltran-Valero de Bernabé D, Sabatelli P, Merlini L et al. POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome. J Med Genet. 2005 doi:10.1136/jmg.2005.031963 PubMed
302. van Reeuwijk J, Maugenre S, van den Elzen C, Verrips A, Bertini E, Muntoni F et al. The expanding phenotype of POMT1 mutations: from Walker-Warburg syndrome to congenital muscular dystrophy, microcephaly, and mental retardation. Hum Mutat. 2006 doi:10.1002/humu.20313 PubMed
303. Van Reeuwijk J, Olderode-Berends MJ, Van den Elzen C, Brouwer OF, Roscioli T, Van Pampus MG et al. A homozygous FKRP start codon mutation is associated with Walker-Warburg syndrome, the severe end of the clinical spectrum. Clin Genet. 2010 doi:10.1111/j.1399-0004.2010.01384.x PubMed
304. Riemersma M, Mandel H, van Beusekom E, Gazzoli I, Roscioli T, Eran A et al. Absence of α- and β-dystroglycan is associated with Walker-Warburg syndrome. Neurology. 2015 doi:10.1212/WNL.0000000000001615 PubMed
305. Saredi S, Ardissone A, Ruggieri A, Mottarelli E, Farina L, Rinaldi R et al. Novel POMGNT1 point mutations and intragenic rearrangements associated with muscle-eye-brain disease. J Neurol Sci. 2012 doi:10.1016/j.jns.2012.04.008 PubMed
306. Vervoort VS, Holden KR, Ukadike KC, Collins JS, Saul RA, Srivastava AK. POMGnT1 gene alterations in a family with neurological abnormalities. Ann Neurol. 2004 doi:10.1002/ana.20172 PubMed
307. Willer T, Lee H, Lommel M, Yoshida-Moriguchi T, de Bernabe DB, Venzke D et al. ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome. Nat Genet. 2012 doi:10.1038/ng.2252 PubMed
308. Yis U, Uyanik G, Kurul S, Dirik E, Ozer E, Gross C et al. A case of Walker-Warburg syndrome resulting from a homozygous POMT1 mutation. Eur J Paediatr Neurol. 2007 doi:10.1016/j.ejpn.2006.10.007 PubMed
309. Yoshida A, Kobayashi K, Manya H, Taniguchi K, Kano H, Mizuno M et al. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell. 2001 doi:10.1016/S1534-5807(01)00070-3 PubMed
310. Abdel-Salam GM, Flores-Sarnat L, El-Ruby MO, Parboosingh J, Bridge P, Eid MM et al. Muenke syndrome with pigmentary disorder and probable hemimegalencephaly: An expansion of the phenotype. Am J Med Genet A. 2011 doi:10.1002/ajmg.a.33777 PubMed
311. Arnaud-López L, Fragoso R, Mantilla-Capacho J, Barros-Núñez P. Crouzon with acanthosis nigricans. Further delineation of the syndrome. Clin Genet. 2007 doi:10.1111/j.1399-0004.2007.00884.x PubMed
312. Chen CP, Chern SR, Shih JC, Wang W, Yeh LF, Chang TY et al. Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia. Prenat Diagn. 2001 doi:10.1002/1097-0223(200102)21:2<89::AID-PD21>3.0.CO;2-9 PubMed
313. Chen CP, Lin SP, Su YN, Chien SC, Tsai FJ, Wang W. Craniosynostosis and congenital tracheal anomalies in an infant with Pfeiffer syndrome carrying the W290C FGFR2 mutation. Genet Couns. 2008 PubMed
314. Chen CP, Lin SP, Liu YP, Chern SR, Chen SW, Lai ST et al. Pfeiffer syndrome with FGFR2 C342R mutation presenting extreme proptosis, craniosynostosis, hearing loss, ventriculomegaly, broad great toes and thumbs, maxillary hypoplasia, and laryngomalacia. Taiwan J Obstet Gynecol. 2017 doi:10.1016/j.tjog.2017.04.030 PubMed
315. Fonseca R, Costa-Lima MA, Cosentino V, Orioli IM. Second case of Beare-Stevenson syndrome with an FGFR2 Ser372Cys mutation. Am J Med Genet A. 2008 doi:10.1002/ajmg.a.32176 PubMed
316. González-Del-Angel A, Estandía-Ortega B, Alcántara-Ortigoza MA, Martínez-Cruz V, Gutiérrez-Tinajero DJ, Rasmussen A et al. Expansion of the variable expression of Muenke syndrome: Hydrocephalus without craniosynostosis. Am J Med Genet A. 2016 doi:10.1002/ajmg.a.37951 PubMed
317. Gripp KW, Stolle CA, McDonald-McGinn DM, Markowitz RI, Bartlett SP, Katowitz JA et al. Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III. Am J Med Genet. 1998 doi:10.1002/(SICI)1096-8628(19980724)78:4<356::AID-AJMG10>3.0.CO;2-H PubMed
318. Gupta S, Prasad A, Sinha U, Singh R, Gupta G. Crouzon syndrome in a ten-week-old infant: a case report. Saudi J Med Med Sci. 2020 doi:10.4103/sjmms.sjmms_38_19 PubMed
319. Lajeunie E, Heuertz S, El Ghouzzi V, Martinovic J, Renier D, Le Merrer M et al. Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome. Eur J Human Genet. 2006 doi:10.1038/sj.ejhg.5201558 PubMed
320. Priolo M, Lerone M, Baffico M, Baldi M, Ravazzolo R, Cama A et al. Pfeiffer syndrome type 2 associated with a single amino acid deletion in the FGFR2 gene. Clin Genet. 2000 doi:10.1034/j.1399-0004.2000.580116.x PubMed
321. Przylepa KA, Paznekas W, Zhang M, Golabi M, Bias W, Bamshad MJ et al. Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome. Nat Genet. 1996 doi:10.1038/ng0896-492 PubMed
322. Rump P, Letteboer TG, Gille JJ, Torringa MJ, Baerts W, van Gestel JP et al. Severe complications in a child with achondroplasia and two FGFR3 mutations on the same allele. Am J Med Genet A. 2006 doi:10.1002/ajmg.a.31084 PubMed
323. Rutland P, Pulleyn LJ, Reardon W, Baraitser M, Hayward R, Jones B et al. Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes. Nat Genet. 1995 doi:10.1038/ng0295-173 PubMed
324. Schaefer F, Anderson C, Can B, Say B. Novel mutation in the FGFR2 gene at the same codon as the Crouzon syndrome mutations in a severe Pfeiffer syndrome type 2 case. Am J Med Genet. 1998 doi:10.1002/(SICI)1096-8628(19980123)75:3<252::AID-AJMG4>3.0.CO;2-S PubMed
325. Takenouchi T, Hida M, Sakamoto Y, Torii C, Kosaki R, Takahashi T et al. Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype. Am J Med Genet A. 2013 doi:10.1002/ajmg.a.36157 PubMed
326. Çiftçi E, Ince E, Akar N, Dogru Ü, Tefs K, Schuster V. Ligneous conjunctivitis, hydrocephalus, hydrocele, and pulmonary involvement in a child with homozygous type I plasminogen deficiency. Eur J Pediatr. 2003 doi:10.1007/s00431-003-1205-z PubMed
327. Cormand B, Avela K, Pihko H, Santavuori P, Talim B, Topaloglu H et al. Assignment of the muscle-eye-brain disease gene to 1p32-p34 by linkage analysis and homozygosity mapping. Am J Hum Genet. 1999 doi:10.1086/302206 PubMed
328. Cotarelo RP, Valero MC, Prados B, Peña A, Rodríguez L, Fano O et al. Two new patients bearing mutations in the fukutin gene confirm the relevance of this gene in Walker-Warburg syndrome. Clin Genet. 2008 doi:10.1111/j.1399-0004.2007.00936.x PubMed
329. de Bernabé DB, van Bokhoven H, van Beusekom E, Van den Akker W, Kant S, Dobyns WB et al. A homozygous nonsense mutation in the fukutin gene causes a Walker-Warburg syndrome phenotype. J Med Genet. 2003 doi:10.1136/jmg.40.11.845 PubMed
330. Horn D, Robinson PN. Progeroid facial features and lipodystrophy associated with a novel splice site mutation in the final intron of the FBN1 gene. Am J Med Genet A. 2011 doi:10.1002/ajmg.a.33905 PubMed
331. Kondo-Iida E, Kobayashi K, Watanabe M, Sasaki J, Kumagai T, Koide H et al. Novel mutations and genotype-phenotype relationships in 107 families with Fukuyama-type congenital muscular dystrophy (FCMD). Hum Mol Genet. 1999 doi:10.1093/hmg/8.12.2303 PubMed
332. Radmanesh F, Caglayan AO, Silhavy JL, Yilmaz C, Cantagrel V, Omar T et al. Mutations in LAMB1 cause cobblestone brain malformation without muscular or ocular abnormalities. Am J Hum Genet. 2013 doi:10.1016/j.ajhg.2013.02.005 PubMed
333. Saito K, Osawa M, Wang ZP, Ikeya K, Fukuyama Y, Kondo-Iida E et al. Haplotype-phenotype correlation in Fukuyama congenital muscular dystrophy. Am J Med Genet. 2000 doi:10.1002/(SICI)1096-8628(20000529)92:3<184::AID-AJMG5>3.0.CO;2-N PubMed
334. Schott D, Dempfle CE, Beck P, Liermann A, Mohr-Pennert A, Goldner M et al. Therapy with a purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency. N Engl J Med. 1998 doi:10.1056/NEJM199812033392305 PubMed
335. Schuster V, Mingers AM, Seidenspinner S, Nüssgens Z, Pukrop T, Kreth HW. Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis. Blood. 1997 doi:10.1182/blood.V90.3.958 PubMed
336. Schuster V, Seidenspinner S, Müller C, Rempen A. Prenatal diagnosis in a family with severe type I plasminogen deficiency, ligneous conjunctivitis and congenital hydrocephalus. Prenat Diagn. 1999 doi:10.1002/(SICI)1097-0223(199905)19:5<483::AID-PD575>3.0.CO;2-H PubMed
337. Tonduti D, Dorboz I, Renaldo F, Masliah-Planchon J, Elmaleh-Bergès M, Dalens H et al. Cystic leukoencephalopathy with cortical dysplasia related to LAMB1 mutations. Neurology. 2015 doi:10.1212/WNL.0000000000001607 PubMed
338. van der Knaap MS, Smit LM, Barkhof F, Pijnenburg YA, Zweegman S, Niessen HW et al. Neonatal porencephaly and adult stroke related to mutations in collagen IV A1. Ann Neurol. 2006 doi:10.1002/ana.20715 PubMed
339. Yang YD, Huang LY, Yan JM, Han J, Zhang Y, Li DZ. Novel FREM1 mutations are associated with severe hydrocephalus and shortened limbs in a prenatal case. Eur J Obstet Gynecol Reprod Biol. 2017 doi:10.1016/j.ejogrb.2017.06.017 PubMed
340. Antwi P, Hong CS, Duran D, Jin SC, Dong W, DiLuna M et al. A novel association of campomelic dysplasia and hydrocephalus with an unbalanced chromosomal translocation upstream of SOX9. Cold Spring Harbor molecular case studies. 2018 doi:10.1101/mcs.a002766 PubMed
341. Avitan-Hersh E, Mandel H, Indelman M, Bar-Joseph G, Zlotogorski A, Bergman R. A case of H syndrome showing immunophenotye similarities to Rosai-Dorfman disease. Am J Dermatopathol. 2011 doi:10.1097/DAD.0b013e3181ee547c PubMed
342. Cauley ES, Hamed A, Mohamed IN, Elseed M, Martinez S, Yahia A et al. Overlap of polymicrogyria, hydrocephalus, and Joubert syndrome in a family with novel truncating mutations in ADGRG1/GPR56 and KIAA0556. Neurogenetics. 2019 doi:10.1007/s10048-019-00577-2 PubMed
343. Christofolini DM, Yoshimoto M, Squire JA, Brunoni D, Melaragno MI, Carvalheira G. Hydrocephaly, penoscrotal transposition, and digital anomalies associated with de novo pseudodicentric rearranged chromosome 13 characterized by classical cytogenetic methods and mBAND analysis. Am J Med Genet A. 2006 doi:10.1002/ajmg.a.31269 PubMed
344. Doherty D, Chudley AE, Coghlan G, Ishak GE, Innes AM, Lemire EG et al. GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome. Am J Hum Genet. 2012 doi:10.1016/j.ajhg.2012.04.008 PubMed
345. Forrester S, Kovach MJ, Smith RE, Rimer L, Wesson M, Kimonis VE. Kousseff syndrome caused by deletion of chromosome 22q11-13. Am J Med Genet. 2002 doi:10.1002/ajmg.10625 PubMed
346. Grosso S, Cioni M, Garibaldi G, Pucci L, Galluzzi P, Canapicchi R et al. De novo complete trisomy 5p: clinical and neuroradiological findings. Am J Med Genet. 2002 doi:10.1002/ajmg.10679 PubMed
347. Jacquemin V, Antoine M, Duerinckx S, Massart A, Desir J, Perazzolo C et al. TrkA mediates effect of novel KIDINS220 mutation in human brain ventriculomegaly. Hum Mol Genet. 2021 doi:10.1093/hmg/ddaa245 PubMed
348. Kline-Fath BM, Merrow AC, Calvo-Garcia MA, Nagaraj UD, Saal HM. Fowler syndrome and fetal MRI findings: a genetic disorder mimicking hydranencephaly/hydrocephalus. Pediatr Radiol. 2018 doi:10.1007/s00247-018-4106-z PubMed
349. Koenigstein K, Gramsch C, Kolodziej M, Neubauer BA, Weber A, Lechner S et al. Chudley-McCullough syndrome: variable clinical picture in twins with a novel GPSM2 mutation. Neuropediatrics. 2016 doi:10.1055/s-0036-1579785 PubMed
350. Lahiry P, Wang J, Robinson JF, Turowec JP, Litchfield DW, Lanktree MB et al. A multiplex human syndrome implicates a key role for intestinal cell kinase in development of central nervous, skeletal, and endocrine systems. Am J Hum Genet. 2009 doi:10.1016/j.ajhg.2008.12.017 PubMed
351. Li Y, Choy KW, Xie HN, Chen M, He WY, Gong YF et al. Congenital hydrocephalus and hemivertebrae associated with de novo partial monosomy 6q (6q253→qter). Balkan J Med Genet. 2015 doi:10.1515/bjmg-2015-0009 PubMed
352. K. Maclean, J. Smith, L. St Heaps, N. Chia, R. Williams, G.B. Peters, E. Onikul, T. McCrossin, O.J. Lehmann, and L.C. Adès, Axenfeld-Rieger malformation and distinctive facial features: Clues to a recognizable 6p25 microdeletion syndrome. Am J Med Genet A 132 (2005) 381–5.10.1002/ajmg.a.3027415654696 doi:10.1002/ajmg.a.30274 PubMed
353. Mero IL, Mørk HH, Sheng Y, Blomhoff A, Opheim GL, Erichsen A et al. Homozygous KIDINS220 loss-of-function variants in fetuses with cerebral ventriculomegaly and limb contractures. Hum Mol Genet. 2017 doi:10.1093/hmg/ddx263 PubMed
354. Pappa L, Kals M, Kivistik PA, Metspalu A, Paal A, Nikopensius T. Exome analysis in an Estonian multiplex family with neural tube defects-a case report. Childs Nerv Syst. 2017 doi:10.1007/s00381-017-3491-1 PubMed
355. Powis Z, Chamberlin AC, Alamillo CL, Ceulemans S, Bird LM, Tang S. Postmortem diagnostic exome sequencing identifies a de novo TUBB3 alteration in a newborn with prenatally diagnosed hydrocephalus and suspected walker-warburg syndrome. Pediatr Dev Pathol. 2018 doi:10.1177/1093526617698611 PubMed
356. Rai B, Sharif F. Cervicomedullary spinal stenosis and ventriculomegaly in a child with developmental delay due to chromosome 16p12.1 microdeletion syndrome. J Child Neurol. 2015 doi:10.1177/0883073814533149 PubMed
357. Su J, Lu W, Li M, Zhang Q, Chen F, Yi S et al. Novel compound heterozygous frameshift variants in WDR81 associated with congenital hydrocephalus 3 with brain anomalies: First Chinese prenatal case confirms WDR81 involvement. Mol Genet Genomic Med. 2021 doi:10.1002/mgg3.1624 PubMed
358. Yüksel Z, Vogel F, Alhashem AM, Alanzi TSA, Tabarki B, Kampe K et al. A homozygous frameshift variant in an alternatively spliced exon of DLG5 causes hydrocephalus and renal dysplasia. Clin Genet. 2019 doi:10.1111/cge.13513 PubMed
359. Demir HA, Varan A, Utine EG, Aktaş D, Oğuz B, Rama D et al. WAGR syndrome with tetralogy of Fallot and hydrocephalus. J Pediatr Hematol Oncol. 2011 doi:10.1097/MPH.0b013e3182114e0e PubMed
360. Fukino K, Teramoto A, Adachi K, Takahashi H, Emi M. A family with hydrocephalus as a complication of cerebellar hemangioblastoma: identification of Pro157Leu mutation in the VHL gene. J Hum Genet. 2000 doi:10.1007/s100380050009 PubMed
361. Kusakabe K, Kohno S, Inoue A, Seno T, Yonezawa S, Moritani K et al. Combined morphological, immunohistochemical and genetic analyses of medulloepithelioma in the posterior cranial fossa. Neuropathology. 2018 doi:10.1111/neup.12431 PubMed
362. Reardon W, Zhou XP, Eng C. A novel germline mutation of the PTEN gene in a patient with macrocephaly, ventricular dilatation, and features of VATER association. J Med Genet. 2001 doi:10.1136/jmg.38.12.820 PubMed
363. Uguen A, Laurent C, Samaison L, Boisselier B, Talagas M, Costa S et al. Severe hydrocephalus caused by diffuse leptomeningeal and neurocutaneous melanocytosis of antenatal onset: a clinical, pathologic, and molecular study of 2 cases. Hum Pathol. 2015 doi:10.1016/j.humpath.2015.04.013 PubMed
364. Drielsma A, Jalas C, Simonis N, Désir J, Simanovsky N, Pirson I et al. Two novel CCDC88C mutations confirm the role of DAPLE in autosomal recessive congenital hydrocephalus. J Med Genet. 2012 doi:10.1136/jmedgenet-2012-101190 PubMed
365. Ruggeri G, Timms AE, Cheng C, Weiss A, Kollros P, Chapman T et al. Bi-allelic mutations of CCDC88C are a rare cause of severe congenital hydrocephalus. Am J Med Genet A. 2018 doi:10.1002/ajmg.a.38592 PubMed
366. Wallis M, Baumer A, Smaili W, Jaouad IC, Sefiani A, Jacobson E et al. Surprisingly good outcome in antenatal diagnosis of severe hydrocephalus related to CCDC88C deficiency. Eur J Med Genet. 2018 doi:10.1016/j.ejmg.2017.12.002 PubMed
367. Chen CP, Ko TM, Wang LK, Chern SR, Wu PS, Chen SW et al. Prenatal diagnosis and molecular cytogenetic characterization of a chromosome 1q42.3-q44 deletion in a fetus associated with ventriculomegaly on prenatal ultrasound. Taiwan J Obstet Gynecol. 2020 doi:10.1016/j.tjog.2020.05.022 PubMed
368. Diets IJ, Prescott T, Champaigne NL, Mancini GMS, Krossnes B, Frič R et al. A recurrent de novo missense pathogenic variant in SMARCB1 causes severe intellectual disability and choroid plexus hyperplasia with resultant hydrocephalus. Genet Med. 2019 doi:10.1038/s41436-018-0079-4 PubMed
369. Negishi Y, Miya F, Hattori A, Mizuno K, Hori I, Ando N et al. Truncating mutation in NFIA causes brain malformation and urinary tract defects. Hum Genome Var. 2015 doi:10.1038/hgv.2015.7 PubMed
370. Nyboe D, Kreiborg S, Kirchhoff M, Hove HB. Familial craniosynostosis associated with a microdeletion involving the NFIA gene. Clin Dysmorphol. 2015 doi:10.1097/MCD.0000000000000079 PubMed
371. Shtaya A, Elmslie F, Crow Y, Hettige S. Leukoencephalopathy, Intracranial Calcifications, Cysts, and SNORD118 Mutation (Labrune Syndrome) with Obstructive Hydrocephalus. World Neurosurg. 2019 doi:10.1016/j.wneu.2019.02.008 PubMed
372. Verkerk AJ, Schot R, van Waterschoot L, Douben H, Poddighe PJ, Lequin MH et al. Unbalanced der(5)t(5;20) translocation associated with megalencephaly, perisylvian polymicrogyria, polydactyly and hydrocephalus. Am J Med Genet A. 2010 doi:10.1002/ajmg.a.33408 PubMed
373. A. Vetro, M. Iascone, I. Limongelli, N. Ameziane, S. Gana, E. Della Mina, U. Giussani, R. Ciccone, A. Forlino, L. Pezzoli, M.A. Rooimans, A.J. van Essen, J. Messa, T. Rizzuti, P. Bianchi, J. Dorsman, J.P. de Winter, F. Lalatta, and O. Zuffardi. Loss-of-Function FANCL Mutations Associate with Severe Fanconi Anemia Overlapping the VACTERL Association. Hum Mutat 36 (2015) 562–8.10.1002/humu.2278425754594 doi:10.1002/humu.22784 PubMed
374. Zechi-Ceide RM, Guion-Almeida ML, de Rodini ES, Jesus-Oliveira NA, Passos-Bueno MR. Hydrocephalus and moderate mental retardation in a boy with Van der Woude phenotype and IRF6 gene mutation. Clin Dysmorphol. 2007 doi:10.1097/MCD.0b013e3280739753 PubMed
375. Castañeyra-Ruiz L, González-Marrero I, González-Toledo JM, Castañeyra-Ruiz A, de Paz-Carmona H, Castañeyra-Perdomo A et al. Aquaporin-4 expression in the cerebrospinal fluid in congenital human hydrocephalus. Fluids Barriers CNS. 2013 doi:10.1186/2045-8118-10-18 PubMed
376. Kvarnung M, Taylan F, Nilsson D, Albåge M, Nordenskjöld M, Anderlid BM et al. Mutations in FLVCR2 associated with Fowler syndrome and survival beyond infancy. Clin Genet. 2016 doi:10.1111/cge.12565 PubMed
377. Lalonde E, Albrecht S, Ha KC, Jacob K, Bolduc N, Polychronakos C et al. Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing. Hum Mutat. 2010 doi:10.1002/humu.21293 PubMed
378. Martínez-Glez V, Romanelli V, Mori MA, Gracia R, Segovia M, González-Meneses A et al. Macrocephaly-capillary malformation: Analysis of 13 patients and review of the diagnostic criteria. Am J Med Genet A. 2010 doi:10.1002/ajmg.a.33514 PubMed
379. Özdemir M, Çırali C, Yılmaz-Ağladıoğlu S, Evrengül H, Tepeli E, Ergin H. Neonatal Bartter syndrome with cholelithiasis and hydrocephalus: rare association. Pediatr Int. 2016 doi:10.1111/ped.12999 PubMed
380. Thomas S, Encha-Razavi F, Devisme L, Etchevers H, Bessieres-Grattagliano B, Goudefroye G et al. High-throughput sequencing of a 41 Mb linkage interval reveals FLVCR2 deletions and mutations in lethal cerebral vasculopathy. Hum Mutat. 2010 doi:10.1002/humu.21329 PubMed
381. Visapää I, Salonen R, Varilo T, Paavola P, Peltonen L. Assignment of the locus for hydrolethalus syndrome to a highly restricted region on 11q23-25. Am J Hum Genet. 1999 doi:10.1086/302603 PubMed
382. Morimoto Y, Yoshida S, Kinoshita A, Satoh C, Mishima H, Yamaguchi N et al. Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities. Neurology. 2019 doi:10.1212/WNL.0000000000007505 PubMed
383. Zhang J, Carr CW, Rigamonti D, Badr A. Genome-wide linkage scan maps ETINPH gene to chromosome 19q12–1331. Hum Hered. 2010 doi:10.1159/000288711 PubMed
384. Schaaf CP, Koster J, Katsonis P, Kratz L, Shchelochkov OA, Scaglia F et al. Desmosterolosis-phenotypic and molecular characterization of a third case and review of the literature. Am J Med Genet A. 2011 doi:10.1002/ajmg.a.34040 PubMed
385. Alazami AM, Patel N, Shamseldin HE. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 2015 doi:10.1016/j.celrep.2014.12.015 PubMed
386. Houge G, Haesen D, Vissers LE, Mehta S, Parker MJ, Wright M et al. B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability. J Clin Invest. 2015 doi:10.1172/JCI79860 PubMed
387. Ouyang L, Yang F. Cole-Carpenter syndrome-1 with a de novo heterozygous deletion in the P4HB gene in a Chinese girl: a case report. Medicine (Baltimore). 2017 doi:10.1097/MD.0000000000009504 PubMed
388. Rauch F, Fahiminiya S, Majewski J, Carrot-Zhang J, Boudko S, Glorieux F et al. Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB. Am J Hum Genet. 2015 doi:10.1016/j.ajhg.2014.12.027 PubMed
389. Slavotinek A, Kaylor J, Pierce H, Cahr M, DeWard SJ, Schneidman-Duhovny D et al. CRB2 mutations produce a phenotype resembling congenital nephrosis, Finnish type, with cerebral ventriculomegaly and raised alpha-fetoprotein. Am J Hum Genet. 2015 doi:10.1016/j.ajhg.2014.11.013 PubMed
390. Zhang L, Zhang Z, Bi X, Mao Y, Cheng Y, Zhu P et al. Genetic and preimplantation diagnosis of cystic kidney disease with ventriculomegaly. J Hum Genet. 2020 doi:10.1038/s10038-020-0731-0 PubMed
391. Meszarosova AU, Lastuvkova J, Rennerova L, Hitka P, Cihlar F, Seeman P et al. Two novel pathogenic variants in KIAA1109 causing Alkuraya-Kučinskas syndrome in two Czech Roma brothers. Clin Dysmorphol. 2020 doi:10.1097/MCD.0000000000000335 PubMed
392. Shiihara T, Oka A, Suzaki I, Ida H, Takeshita K. Communicating hydrocephalus in a patient with Gaucher's disease type 3. Pediatr Neurol. 2000 doi:10.1016/S0887-8994(99)00140-X PubMed
393. Basel-Vanagaite L, Raas-Rotchild A, Kornreich L, Har-Zahav A, Yeshaya J, Latarowski V et al. Familial hydrocephalus with normal cognition and distinctive radiological features. Am J Med Genet A. 2010 doi:10.1002/ajmg.a.33688 PubMed
394. Bernstock JD, Tafel I, Segar DJ, Dowd R, Kappel A, Chen JA et al. Complex management of hydrocephalus secondary to choroid plexus hyperplasia. World neurosurgery. 2020 doi:10.1016/j.wneu.2020.05.211 PubMed
395. Boxill M, Becher N, Sunde L, Thelle T. Choroid plexus hyperplasia and chromosome 9p gains. Am J Med Genet A. 2018 doi:10.1002/ajmg.a.38697 PubMed
396. Brock JA, Dyack S, Ludman M, Dumas N, Gaudet M, Morash B. Mosaic tetrasomy 5p resulting from an isochromosome 5p marker chromosome: case report and review of literature. Am J Med Genet A. 2012 doi:10.1002/ajmg.a.34272 PubMed
397. Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T et al. Recurrent reciprocal 1q211 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet. 2008 doi:10.1038/ng.279 PubMed
398. Cai M, Huang H, Xu L, Lin N. Classifying and evaluating fetuses with ventriculomegaly in genetic etiologic studies. Front Genet. 2021 doi:10.3389/fgene.2021.682707 PubMed
399. Cambosu F, Capobianco G, Fogu G, Bandiera P, Pirino A, Moro MA et al. Partial trisomy of the long arm of chromosome 1: prenatal diagnosis, clinical evaluation and cytogenetic findings Case report and review of the literature. J Obstet Gynaecol Res. 2013 doi:10.1111/j.1447-0756.2012.01986.x PubMed
400. Capra V, De Marco P, Merello E, Baffico AM, Baldi M, Divizia MT et al. Craniosynostosis, hydrocephalus, Chiari I malformation and radioulnar synostosis: probably a new syndrome. Eur J Med Genet. 2009 doi:10.1016/j.ejmg.2008.10.005 PubMed
401. Castro-Gago M, Pintos-Martínez E, Forteza-Vila J, Iglesias-Diz M, Ucieda-Somoza R, Silva-Villar I et al. Congenital hydranencephalic-hydrocephalic syndrome with proliferative vasculopathy: a possible relation with mitochondrial dysfunction. J Child Neurol. 2001 doi:10.1177/08830738010160111401 PubMed
402. Chen CP, Su YN, Hsu CY, Liu YP, Chern SR, Chen LF et al. Prenatal diagnosis of a de novo 17p131 microduplication in a fetus with ventriculomegaly and lissencephaly. Taiwan J Obstet Gynecol. 2011 doi:10.1016/j.tjog.2011.10.032 PubMed
403. Chen CP, Chang TY, Chen YY, Chern SR, Su JW, Wang W. VACTERL association with hydrocephalus in a fetus conceived by in vitro fertilization and embryo transfer. Taiwan J Obstet Gynecol. 2013 doi:10.1016/j.tjog.2013.10.022 PubMed
404. Descipio C, Schneider L, Young TL, Wasserman N, Yaeger D, Lu F et al. Subtelomeric deletions of chromosome 6p: molecular and cytogenetic characterization of three new cases with phenotypic overlap with Ritscher-Schinzel (3C) syndrome. Am J Med Genet A. 2005 doi:10.1002/ajmg.a.30573 PubMed
405. Dubé P, Der Kaloustian VM, Demczuk S, Saabti H, Koenekoop RK. A new association of congenital hydrocephalus, albinism, megalocornea, and retinal coloboma in a syndromic child: a clinical and genetic study. Ophthalmic Genet. 2000 doi:10.1076/1381-6810(200012)2141-HFT211 PubMed
406. Forcelini CM, Mallmann AB, Crusius PS, Seibert CA, Crusius MU, Zandoná DI et al. Down syndrome with congenital hydrocephalus: case report. Arq Neuropsiquiatr. 2006 doi:10.1590/S0004-282X2006000500031 PubMed
407. Garavelli L, Guareschi E, Errico S, Simoni A, Bergonzini P, Zollino M et al. Megalencephaly and perisylvian polymicrogyria with postaxial polydactyly and hydrocephalus (MPPH): report of a new case. Neuropediatrics. 2007 doi:10.1055/s-2007-985908 PubMed
408. Inui K, Yanagihara K, Otani K, Suzuki Y, Akagi M, Nakayama M et al. A new variant neuropathic type of Gaucher's disease characterized by hydrocephalus, corneal opacities, deformed toes, and fibrous thickening of spleen and liver capsules. J Pediatr. 2001 doi:10.1067/mpd.2001.109789 PubMed
409. Kariminejad A, Radmanesh F, Rezayi AR, Tonekaboni SH, Gleeson JG. Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome: a case report. J Child Neurol. 2013 doi:10.1177/0883073812448530 PubMed
410. Lemire EG, Stoeber GP. Chudley-McCullough syndrome: bilateral sensorineural deafness, hydrocephalus, and other structural brain abnormalities. Am J Med Genet. 2000 doi:10.1002/(SICI)1096-8628(20000117)90:2<127::AID-AJMG8>3.0.CO;2-E PubMed
411. Lowry RB, Gould DB, Walter MA, Savage PR. Absence of PITX2, BARX1, and FOXC1 mutations in De Hauwere syndrome (Axenfeld-Rieger anomaly, hydrocephaly, hearing loss): a 25-year follow up. Am J Med Genet A. 2007 doi:10.1002/ajmg.a.31732 PubMed
412. Matteucci F, Tarantino E, Bianchi MC, Cingolani C, Fattori B, Nacci A et al. Sensorineural deafness, hydrocephalus and structural brain abnormalities in two sisters: the Chudley-McCullough syndrome. Am J Med Genet A. 2006 doi:10.1002/ajmg.a.31178 PubMed
413. Naritomi K, Shiroma N, Izumikawa Y, Sameshima K, Ohdo S, Hirayama K. 16q21 is critical for 16q deletion syndrome. Clin Genet. 1988 doi:10.1111/j.1399-0004.1988.tb03464.x PubMed
414. Østergaard E, Pedersen VF, Skriver EB, Brøndum-Nielsen K. Brothers with Chudley-McCullough syndrome: sensorineural deafness, agenesis of the corpus callosum, and other structural brain abnormalities. Am J Med Genet A. 2004 doi:10.1002/ajmg.a.20380 PubMed
415. Remes AM, Rantala H, Hiltunen JK, Leisti J, Ruokonen A. Fumarase deficiency: two siblings with enlarged cerebral ventricles and polyhydramnios in utero. Pediatrics. 1992 doi:10.1542/peds.89.4.730 PubMed
416. Silan F, Yoshioka M, Kobayashi K, Simsek E, Tunc M, Alper M et al. A new mutation of the fukutin gene in a non-Japanese patient. Ann Neurol. 2003 doi:10.1002/ana.10491 PubMed
417. Tohyama J, Akasaka N, Saito N, Yoshimura J, Nishiyama K, Kato M. Megalencephaly and polymicrogyria with polydactyly syndrome. Pediatr Neurol. 2007 doi:10.1016/j.pediatrneurol.2007.04.008 PubMed
418. Toren A, Alpern S, Berkenstadt M, Bar-Yosef O, Pras E, Katorza E. Chromosomal Microarray Evaluation of Fetal Ventriculomegaly. Isr Med Assoc J. 2020 PubMed
419. Vincent C, Kalatzis V, Compain S, Levilliers J, Slim R, Graia F et al. A proposed new contiguous gene syndrome on 8q consists of Branchio-Oto-Renal (BOR) syndrome, Duane syndrome, a dominant form of hydrocephalus and trapeze aplasia; implications for the mapping of the BOR gene. Hum Mol Genet. 1994 doi:10.1093/hmg/3.10.1859 PubMed
420. Wadt K, Jensen LN, Bjerglund L, Lundstrøm M, Kirchhoff M, Kjaergaard S. Fetal ventriculomegaly due to familial submicroscopic terminal 6q deletions. Prenat Diagn. 2012 doi:10.1002/pd.3981 PubMed
421. Walker ME, Lynch-Salamon DA, Milatovich A, Saal HM. Prenatal diagnosis of ring chromosome 6 in a fetus with hydrocephalus. Prenat Diagn. 1996 doi:10.1002/(SICI)1097-0223(199609)16:9<857::AID-PD950>3.0.CO;2-J PubMed
422. Wang J, Zhang Z, Li Q, Zhu H, Lai Y, Luo W et al. Prenatal diagnosis of chromosomal aberrations by chromosomal microarray analysis in foetuses with ventriculomegaly. Sci Rep. 2020 doi:10.1038/s41598-020-77400-8 PubMed
423. Welch KO, Tekin M, Nance WE, Blanton SH, Arnos KS, Pandya A. Chudley-McCullough syndrome: expanded phenotype and review of the literature. Am J Med Genet A. 2003 doi:10.1002/ajmg.a.10180 PubMed
424. Yoshioka M, Kuroki S. Clinical spectrum and genetic studies of Fukuyama congenital muscular dystrophy. Am J Med Genet. 1994 doi:10.1002/ajmg.1320530309 PubMed