The genetic landscape of familial congenital hydrocephalus

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Hydrocephalus is defined as an active distension of the ventricular system of the brain due to inadequate passage of cerebrospinal fluid from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.1 Hydrocephalus is a highly morbid condition if not managed appropriately to relieve the central nervous system from the building pressure caused by a distended ventricular system. Environmental and genetic factors are known to play a role in the etiology of hydrocephalus, although their relative contribution varies with age. For example, whereas infections are the leading cause of hydrocephalus in children, single gene mutations are most commonly associated with congenital (prenatal) hydrocephalus.2
Congenital hydrocephalus is a severe birth defect affecting 4.65 per 10,000 births and is associated with high morbidity and mortality.3 Although many syndromes can be associated with congenital hydrocephalus, there are surprisingly very few genes that are known to cause the disease as the sole or primary clinical feature.5L1CAM (MIM 308840) is the best‐known disease gene in congenital hydrocephalus, with an estimated contribution to as many as 30% of suspected X‐linked cases.6 This gene has been linked to a number of neurological phenotypes with or without congenital hydrocephalus, in addition to nonsyndromic congenital hydrocephalus.7AP1S2 (MIM 300629) is another X‐linked gene that has been found to be mutated in patients with congenital hydrocephalus, including those with phenotypes once proposed to be allelic to L1CAM‐related disorders.8 Much less is known about the autosomal contribution to congenital hydrocephalus. In 2010, Ekici et al reported a homozygous truncating mutation in CCDC88C in a consanguineous multiplex family, a finding that was independently confirmed by a subsequent report.10 In 2013, we reported the identification of a novel locus in 2 families with autosomal recessive congenital hydrocephalus.12 A founder homozygous truncating variant in MPDZ was identified in both families. No independent confirmation has been published to date to confirm the candidacy of MPDZ.
Despite the identification of these 4 genes, the genetic landscape of congenital hydrocephalus remains largely unexplored.13 Previous studies have mostly targeted L1CAM sequencing in cohorts of patients with congenital hydrocephalus.6 Pursuing Mendelian causes of congenital hydrocephalus is important because they can expand our knowledge of the molecular underpinning of the disease. It is also a prerequisite for the proper interpretation of genome sequencing in patients with congenital hydrocephalus with the attendant benefit of precise recurrence risk estimate. In this study, we report on the genomic analysis of a relatively large cohort of families with recurrence of congenital hydrocephalus. Our results reveal marked genetic heterogeneity, which we further expand by proposing EML1 and WDR81 as bona fide disease genes in congenital hydrocephalus.
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