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Genetic architecture of primary congenital hydrocephalus

par Jacquemin, Valérie
Président du jury Schiffmann, Serge N.
Promoteur Abramowicz, Marc
Co-Promoteur Pirson, Isabelle
Publication Non publié, 2023-08-28

Thèse de doctorat

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Résumé :

Primary congenital hydrocephalus (PCH) is characterized by ventriculomegaly, defined as a dilation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. PCH, highly heterogenous in etiology, affects 1 in 1,000 live births, where its poor prognosis and lack of satisfactory treatments, underscores our incomplete understanding of PCH pathogenesis. While epidemiological data suggest an underlying genetic cause in up to 40% of congenital hydrocephalus cases, few genes have been discovered as causal of PCH where ventriculomegaly is the sole or primary clinical feature.The work presented within this thesis represents the study through whole-exome sequencing (WES) of a cohort of 28 inbred/outbred families with PCH. Analysis for rare transmitted or de novo mutations (MAF <0.005) uncovered novel mutations in known genes associated with PCH (POMT2, POMGNT1, CRADD, ARID1A and KIDINS220), thus broadening the spectrum of known mutations in PCH. In a consanguineous family we identified a mutation in KIDINS220 shared among the three fetuses presenting brain ventriculomegaly and limb contractures, a gene previously reported in one family with an identical phenotype. Through immunoprecipitation experiments, we showed that the mutation diminished the interaction of KIDINS220 with TrkA, a receptor important in cell survival signaling.In three PCH probands, we identified variants in three potential candidate genes, which reflect the heterogenous genetic landscape of PCH as they are involved in minor spliceosome (RNPC3), angiogenesis (TIE1) and ciliary structure (DNAH2). Though literature poses these genes as strong candidates, further investigation will be required to ascertain them as such.With the increasing number of reports demonstrating that disorders traditionally considered as monogenic are in fact caused by a combination of mutant genes, possible oligogenic inheritance of human PCH was investigated. As ciliary defects of motile and more recently of primary cilia have been associated to the development of hydrocephalus in animal models, we conducted a mutation burden analysis in ciliary genes. This analysis revealed a statistically significant mutation burden in primary cilia genes in PCH patients compared to controls. Then, using a bio-informatic prediction tool for digenic inheritance, individual patient variants in ciliary genes were analyzed, revealing for one proband strong evidence of a true digenic pair. Altogether, these findings suggest, for the first time, that a subset of PCH patients may be associated to oligogenic inheritance involving primary cilia.