[en] [en] 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.
Disciplines :
Genetics & genetic processes
Author, co-author :
JACQUEMIN, VALERIE ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique ; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium. jacqvalli@yahoo.com
Versbraegen, Nassim ; Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium ; Machine Learning Group, Université Libre de Bruxelles, Brussels, Belgium
Duerinckx, Sarah; Service de Neuropédiatrie, Hôpital Universitaire de Bruxelles and CUB Hôpital Erasme and Université Libre de Bruxelles, Brussels, Belgium
Massart, Annick; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium ; Department of Nephrology, University Hospital of Antwerp, Edegem, Belgium
Soblet, Julie; Human Genetics Department, CUB Hôpital Erasme, Brussels, Belgium
Perazzolo, Camille; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium
Deconinck, Nicolas; Hopital Universitaire des Enfants Reine Fabiola and Hopital Universitaire de Bruxelles and Université Libre de Bruxelles, Brussels, Belgium
Brischoux-Boucher, Elise; Centre de génétique humaine - CHU de Besançon, Université de Bourgogne-Franche-Comté, Besançon, France
De Leener, Anne; Centre de Génétique Humaine, Cliniques Universitaires Saint-Luc et Université Catholique de Louvain, Brussels, Belgium
Revencu, Nicole ; Centre de Génétique Humaine, Cliniques Universitaires Saint-Luc et Université Catholique de Louvain, Brussels, Belgium
Janssens, Sandra; Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
Moorgat, Stèphanie; Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium
Blaumeiser, Bettina; Center of Medical Genetics, Antwerp University and Antwerp University Hospital, Edegem, Belgium
Avela, Kristiina; Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland
Touraine, Renaud; Génétique Clinique Chromosomique et Moléculaire, CHU de Saint-Etienne, St-Priest-en-Jarez, France
Abou Jaoude, Imad; Department of Gynecology and Obstetrics, Abou Jaoude Hospital, Jal El Dib, Lebanon
Keymolen, Kathelijn; Center for Medical Genetics, UZ Brussels, Jette, Belgium
Saugier-Veber, Pascale; Department of Genetics and Reference Center for Developmental Disorders, Université Rouen Normandie, Inserm U1245 and CHU Rouen, Rouen, France
Lenaerts, Tom ; Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium ; Machine Learning Group, Université Libre de Bruxelles, Brussels, Belgium ; Artificial Intelligence Lab, Vrije Universiteit Brussel, Brussels, Belgium
Abramowicz, Marc ; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium. marc.abramowicz@unige.ch ; Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. marc.abramowicz@unige.ch
Pirson, Isabelle ; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium
HUDERF - Hôpital Universitaire Des Enfants Reine Fabiola Erasme University Hospital FWB - Fédération Wallonie-Bruxelles
Funding text :
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).
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