Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
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The sequencing data for all CH parent–offspring trios and singletons reported in this study have been deposited in the NCBI Database of Genotypes and Phenotypes under accession number phs000744.v4.p2. Our in-house R and Python pipelines and codes are available upon request.
Our in-house Python and R pipelines are available from the corresponding author on request.
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We are grateful to the patients and their families who participated in this research. We thank the Hydrocephalus Association (HA) for their support. We also thank J. Koschnitzky (HA), J. Rockefeller (Yale), J. Freeman (Yale) and J. Nicolleli (Yale) for their help and support. This work is supported by the Yale–National Institutes of Health (NIH) Center for Mendelian Genomics (5U54HG006504); NIH Director’s Pioneer Award DP1HD086071 and NIH Director’s Transformative Award 1R01AI145057 (S.J.S.); R01 NS111029-01A1, R01 NS109358, K12 228168 and the Rudi Schulte Research Institute (K.K.); NIH Medical Scientist Training Program (NIH/National Institute of General Medical Sciences Grant T32GM007205); NIH Clinical and Translational Science Award from the National Center for Advancing Translational Science (TL1 TR001864); James Hudson Brown – Alexander B. Coxe Fellowship at Yale School of Medicine, the American Heart Association Postdoctoral Fellowship (18POST34060008), the K99/R00 Pathway to Independence Award (K99HL143036 and R00HL143036-02) (S.C.J.); the American Heart Association Predoctoral Fellowship (19PRE34380842, W.D.); the Pediatric Hydrocephalus Foundation (P.H.F.). We thank M. C. Kruer at Phoenix Children’s Hospital and H. Zhao at Yale School of Public Health for critical discussion.
The authors declare no competing interests.
Peer review information Kate Gao and Jerome Staal were the primary editors on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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a, Pedigrees and sequencing electropherograms of Sanger sequencing depict all TRIM71 mutations in genomic DNA from CH probands. b, Representative T1 or T2-weighted brain magnetic resonance images for all available probands.
a, Pedigrees and sequencing electropherograms of Sanger sequencing depict all SMARCC1 mutations in genomic DNA from CH probands. b, Representative T1 or T2-weighted brain magnetic resonance images or head CTs for all available probands.
a, Pedigrees and sequencing electropherograms of Sanger sequencing depict all PIK3CA mutations in genomic DNA from CH probands. b, Representative T1 or T2-weighted brain magnetic resonance images for all available probands.
a, Pedigrees and sequencing electropherograms of Sanger sequencing depict all PTEN mutations in genomic DNA from CH probands. b, Representative T1 or T2-weighted brain magnetic resonance images or head CTs for all available probands.
a, Pedigrees and sequencing electropherograms of Sanger sequencing depict all MTOR mutations in genomic DNA from CH probands. b, Representative T1 or T2-weighted brain magnetic resonance images or head CTs for all available probands.
a, Pedigrees and sequencing electropherograms of Sanger sequencing depict all FOXJ1 mutations in genomic DNA from CH probands. b, Representative T1 or T2-weighted brain magnetic resonance images for all available probands.
a, Pedigrees and sequencing electropherograms of Sanger sequencing depict all FMN2 mutations in genomic DNA from CH probands. b, Representative T1 or T2-weighted brain magnetic resonance images for all available probands. c, The CRYP-SKIP algorithm prediction on splicing defects for FMN2: c.2137-2 A > G.
a, Pedigrees and sequencing electropherograms of Sanger sequencing depict all PTCH1 mutations in genomic DNA from CH probands. b, Representative T1 or T2-weighted brain magnetic resonance images or head CTs for all available probands.
a, Pedigrees and sequencing electropherograms of Sanger sequencing depict all FXYD2 mutations in genomic DNA from CH probands. b, Representative T1 or T2-weighted brain magnetic resonance images for all available probands. c, The CRYP-SKIP algorithm prediction on splicing defects for FXYD2: c.299-1 G > A. d, The CRYP-SKIP algorithm prediction on splicing defects for FXYD2: c.410 + 1 G > A.
Extended Data Fig. 10 Damaging recessive genotypes in human dystroglycanopathy genes and homologs of mouse hydrocephalus genes.
Available clinical-neuroimaging phenotypes of CH probands with damaging recessive mutations.
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Jin, S.C., Dong, W., Kundishora, A.J. et al. Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus. Nat Med 26, 1754–1765 (2020). https://doi.org/10.1038/s41591-020-1090-2
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