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

Sheng Chih Jin, Weilai Dong, Adam J. Kundishora, Shreyas Panchagnula, Andres Moreno-De-Luca, Charuta G. Furey, August A. Allocco, Rebecca L. Walker, Carol Nelson-Williams, Hannah Smith, Ashley Dunbar, Sierra Conine, Qiongshi Lu, Xue Zeng, Michael C. Sierant, James R. Knight, William Sullivan, Phan Q. Duy, Tyrone DeSpenza, Benjamin C. ReevesJason K. Karimy, Arnaud Marlier, Christopher Castaldi, Irina R. Tikhonova, Boyang Li, Helena Perez Peña, James R. Broach, Edith M. Kabachelor, Peter Ssenyonga, Christine Hehnly, Li Ge, Boris Keren, Andrew T. Timberlake, June Goto, Francesco T. Mangano, James M. Johnston, William E. Butler, Benjamin C. Warf, Edward R. Smith, Steven J. Schiff, David D. Limbrick, Gregory Heuer, Eric M. Jackson, Bermans J. Iskandar, Shrikant Mane, Shozeb Haider, Bulent Guclu, Yasar Bayri, Yener Sahin, Charles C. Duncan, Michael L.J. Apuzzo, Michael L. DiLuna, Ellen J. Hoffman, Nenad Sestan, Laura R. Ment, Seth L. Alper, Kaya Bilguvar, Daniel H. Geschwind, Murat Günel, Richard P. Lifton, Kristopher T. Kahle

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1754-1765
Number of pages12
JournalNature Medicine
Issue number11
StatePublished - Nov 2020

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology


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