Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance

Valerie Jacquemin, Nassim Versbraegen, Sarah Duerinckx, Annick Massart, Julie Soblet, Camille Perazzolo, Nicolas Deconinck, Elise Brischoux-Boucher, Anne De Leener, Nicole Revencu, Sandra Janssens, Stèphanie Moorgat, Bettina Blaumeiser, Kristiina Avela, Renaud Touraine, Imad Abou Jaoude, Kathelijn Keymolen, Pascale Saugier-Veber, Tom Lenaerts, Marc AbramowiczIsabelle Pirson

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Background: Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH. Materials and methods: We sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test. Results: In 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls. Conclusion: Our study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.

Original languageEnglish
Article number16
Number of pages14
JournalHuman genomics
Issue number1
Publication statusPublished - Dec 2023

Bibliographical note

Funding Information:
This work was supported by a Jean Van Damme Orphan Disease grant of the Fonds Erasme (MA) and an Action de Recherche Concertée (ARC) of the Belgian Fédération Wallonie-Bruxelles (MA), as well as the Belgian Kids’ Fund of Hôpital Universitaire des Enfants Reine Fabiola (VJ).

Publisher Copyright:
© 2023, The Author(s).

Copyright 2023 Elsevier B.V., All rights reserved.


  • Female
  • Pregnancy
  • Humans
  • Multifactorial Inheritance
  • Mutation
  • Hydrocephalus
  • Consanguinity
  • Databases, Factual


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