Bi‐allelic mutations of CCDC88C are a rare cause of severe congenital hydrocephalus

Abstract

Congenital or infantile hydrocephalus is caused by genetic and non-genetic factors and is highly heterogeneous in etiology. In recent studies, a limited number of genetic causes of hydrocephalus have been identified. To date, recessive mutations in the CCDC88C gene have been identified as a cause of non-syndromic congenital hydrocephalus in three reported families. Here, we report the fourth known family with two affected individuals with congenital hydrocephalus due to a homozygous mutation in the CCDC88C gene identified by whole exome sequencing. Our two newly described children, as well as the previously published ones, all shared several features including severe infantile-onset hydrocephalus, mild to severe intellectual delay, varying degrees of motor delay, and infantile onset seizures. All identified homozygous mutations in CCDC88C abolish the PDZ binding site necessary for proper CCDC88C protein function in the Wnt signaling pathway. Our report further establishes CCDC88C as one of the few known recessive causes of severe prenatal-onset hydrocephalus. Recognition of this syndrome has important diagnostic and genetic implications for families identified in the future.

MT1-MMP deficiency leads to defective ependymal cell maturation, impaired ciliogenesis, and hydrocephalus

“…Hydrocephalus, a common birth defect with an estimated incidence of 1:1000 (1), is characterized by enlarged intracerebral ventricles. It causes convulsions, mental disability, and even death in patients (2).…”

GPCR-independent activation of G proteins promotes apical cell constriction in vivo

“…Despite abundant information on the biochemical and signaling mechanisms of this growing family of regulators, direct in vivo evidence for a physiological process controlled by them is still lacking. We reasoned that DAPLE, a recently identified member of this group of GEFs, might serve as a G protein activator during embryonic morphogenesis based on the observation that congenital mutations in this gene cause neurodevelopmental disorders in humans (Ekici et al, 2010; Drielsma et al, 2012; Ruggeri et al, 2018; Wallis et al, 2018; Zwaveling-Soonawala et al, 2018; e.g., nonsyndromic hydrocephalus). Here, we show that DAPLE is a tissue-specific activator of G proteins that triggers a signaling cascade culminating in the apical constriction of neuroepithelial cells during neurulation.…”

Murine MPDZ ‐linked hydrocephalus is caused by hyperpermeability of the choroid plexus

“…The earliest monogenic link of hydrocephalus had been made to L1CAM (Rosenthal et al , ; Jouet et al , ; Van Camp et al , ; Coucke et al , ), which encodes the L1 neuronal cell adhesion molecule. Subsequent studies identified AP1S2 , a gene of subunit 2 of clathrin‐associated adaptor protein complex 1 (Saillour et al , ; Cacciagli et al , ), and CCDC88C , which encodes DAPLE, a protein involved in Wnt signaling (Ekici et al , ; Drielsma et al , ; Ruggeri et al , ). A more recent gene linked to congenital hydrocephalus is MPDZ , encoding a large modular scaffold protein that consists of 13 PDZ domains and one L27 domain (Ullmer et al , ; Adachi et al , ).…”