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Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Sheng Chih JinWeilai DongAdam J KundishoraShreyas PanchagnulaAndrés Moreno De LucaCharuta G FureyAugust A AlloccoRebecca L WalkerCarol Nelson-WilliamsHannah SmithAshley DunbarSierra ConineQiongshi LuXue ZengMichael C SierantJames R KnightWilliam SullivanPhan Q DuyTyrone DeSpenzaBenjamin C ReevesJason K KarimyArnaud MarlierChristopher CastaldiIrina R TikhonovaBoyang LiHelena Perez PeñaJames R BroachEdith M KabachelorPeter SsenyongaChristine HehnlyLi GeBoris KerenAndrew T TimberlakeJune GotoFrancesco T ManganoJames M JohnstonWilliam E ButlerBenjamin C WarfEdward R SmithSteven J SchiffDavid D LimbrickGregory HeuerEric M JacksonBermans J IskandarShrikant ManeShozeb M HaiderBulent GucluYasar BayriYener SahinCharles C DuncanMichael L J ApuzzoMichael L DiLunaEllen J HoffmanNenad SestanLaura R MentSeth L AlperKaya BilguvarDaniel H GeschwindMurat GünelRichard P LiftonKristopher T Kahle
Published in: Nature medicine (2020)
Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
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