De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus

Abstract

Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10), SMARCC1 (p = 8.15 × 10), and PTCH1 (p = 1.06 × 10). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.

SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus

“…In CH, whole exome sequencing (WES) study in 27 unrelated CH families identified WDR81 (OMIM# 617967) as a novel disease‐causing gene (Shaheen et al, ). Recently, our group performed a trio‐based WES in 177 CH probands—the majority being sporadic—and identified four novel CH risk genes ( TRIM71 , SMARCC1 , PTCH1 , and SHH ) that account for ~10% of studied cases (Furey et al, ). Surprisingly, all four genes are known to regulate neural stem cell (NSC) proliferation and/or differentiation.…”

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

“…A milder phenotype in a non‐consanguineous family was linked to missense mutations and a heterozygous splice site variant (Al‐Jezawi et al , ). The four genes that have been linked to congenital hydrocephalus most recently, TRIM71 , SMARCC1 , PTCH1 , and SHH (Furey et al , ), regulate ventricular zone neural stem cell differentiation. Their loss‐of‐function is thought to result in defective neurogenesis, including ventriculomegaly.…”

GemC1 is a critical switch for neural stem cell generation in the postnatal brain

“…Congenital hydrocephalus is among the most common CNS disorders; however, very few genes have been associated with its development. To identify novel genes implicated in the etiology of the disorder, we performed whole‐exome sequence in a cohort of congenital hydrocephalus patients (Furey et al, ) and identified a patient with a novel damaging mutation (Absent from in ExAC, 1,000 Genomes and EVS databases) in GEMC1 (p.Glu77Gln; Figure A–C). The patient was delivered by elective cesarean section due to macrocephaly and underwent neurosurgical CSF diversion (endoscopic third ventriculostomy) shortly after birth due to the presence of aqueductal stenosis.…”

“…To identify novel genes implicated in the etiology of the disorder, we performed whole-exome sequence in a cohort of congenital hydrocephalus patients (Furey et al, 2018) and identified a patient with a novel damaging mutation (Absent from in ExAC, 1,000 Genomes and EVS databases) in GEMC1 (p.Glu77Gln; Figure 1A and maps to a highly conserved residue of the GemC1 coiled-coil domain, which is essential for the homo-and heterodimerization of Geminin family members (Caillat et al, 2015).…”

“…Multiple animal studies have been conducted to delineate the molecular etiology of hydrocephalus over the years (Fliegauf, Benzing, & Omran, 2007), whereas less is known about the genetic causes of human hydrocephalus (Kousi & Katsanis, 2016). A recent large-scale genomics study uncovered three new genes associated with congenital hydrocephalus (TRIM71, SMARCC1, and PTCH1), each of which impacts NSC fate (Furey et al, 2018).…”