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 KahlePublished 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.
Keyphrases
- cerebrospinal fluid
- room temperature
- late onset
- genome wide
- amyotrophic lateral sclerosis
- stem cells
- newly diagnosed
- single cell
- end stage renal disease
- copy number
- gene expression
- white matter
- ejection fraction
- endothelial cells
- healthcare
- transcription factor
- subarachnoid hemorrhage
- pregnant women
- chronic kidney disease
- cell therapy
- dna methylation
- early onset
- weight gain
- type diabetes
- electronic health record
- patient reported outcomes
- blood brain barrier
- mesenchymal stem cells
- bioinformatics analysis
- big data
- brain injury
- skeletal muscle
- metabolic syndrome
- genome wide identification
- data analysis
- multiple sclerosis
- physical activity
- pluripotent stem cells
- robot assisted