The genetic landscape of familial congenital hydrocephalus

TLDR

Congenital hydrocephalus is a significant birth defect whose genetics remain largely unknown, with only four Mendelian genes (L1CAM, AP1S2, CCDC88C, MPDZ) previously identified. The study aimed to determine the genetic causes of familial congenital hydrocephalus, assuming these cases represent Mendelian disease forms. Researchers performed exome sequencing, supplemented by positional mapping where appropriate, to identify pathogenic variants. They found likely causal mutations in 78 % of families (21 of 27) across 16 genes, none X‑linked, with ciliopathies and dystroglycanopathies being the most frequent causes, and identified novel associations with EML1 and WDR81 while confirming MPDZ’s role, underscoring the importance of recessive mutations and expanding the disease’s genetic heterogeneity. Published in Annals of Neurology, 2017;81:890–897.

Abstract

Objective Congenital hydrocephalus is an important birth defect, the genetics of which remains incompletely understood. To date, only 4 genes are known to cause Mendelian diseases in which congenital hydrocephalus is the main or sole clinical feature, 2 X‐linked ( L1CAM and AP1S2 ) and 2 autosomal recessive ( CCDC88C and MPDZ ). In this study, we aimed to determine the genetic etiology of familial congenital hydrocephalus with the assumption that these cases represent Mendelian forms of the disease. Methods Exome sequencing combined, where applicable, with positional mapping. Results We identified a likely causal mutation in the majority of these families (21 of 27, 78%), spanning 16 genes, none of which is X‐linked. Ciliopathies and dystroglycanopathies were the most common etiologies of congenital hydrocephalus in our cohort (19% and 26%, respectively). In 1 family with 4 affected members, we identified a homozygous truncating variant in EML1 , which we propose as a novel cause of congenital hydrocephalus in addition to its suggested role in cortical malformation. Similarly, we show that recessive mutations in WDR81 , previously linked to cerebellar ataxia, mental retardation, and disequilibrium syndrome 2, cause severe congenital hydrocephalus. Furthermore, we confirm the previously reported candidacy of MPDZ by presenting a phenotypic spectrum of congenital hydrocephalus associated with 5 recessive alleles. Interpretation Our study highlights the importance of recessive mutations in familial congenital hydrocephalus and expands the locus heterogeneity of this condition. Ann Neurol 2017;81:890–897