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

Authors

• Sheng Chih Jin, Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
• Weilai Dong, Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
• Adam J. Kundishora, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Shreyas Panchagnula, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Andres Moreno-De-Luca, Autism & Developmental Medicine Institute, Genomic Medicine Institute, Department of Radiology, Geisinger, Danville, PA, USA.
• Charuta G. Furey, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• August A. Allocco, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Rebecca L. Walker, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
• Carol Nelson-Williams, Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
• Hannah Smith, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Ashley Dunbar, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Sierra Conine, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Qiongshi Lu, Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, WI, USA.
• Xue Zeng, Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
• Michael C. Sierant, Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
• James R. Knight, Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
• William Sullivan, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Phan Q. Duy, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Tyrone DeSpenza, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Benjamin C. Reeves, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Jason K. Karimy, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Arnaud Marlier, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
• Christopher Castaldi, Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
• Irina R. Tikhonova, Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
• Boyang Li, Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
• Helena Perez Peña, Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, London, UK.
• James R. Broach, Institute for Personalized Medicine, The Penn State College of Medicine, Hershey, PA, USA.
• Edith M. Kabachelor, CURE Children's Hospital of Uganda, Mbale, Uganda.
• Peter Ssenyonga, CURE Children's Hospital of Uganda, Mbale, Uganda.
• Christine Hehnly, Departments of Neurosurgery, Engineering Science & Mechanics, and Physics; Center for Neural Engineering and Infectious Disease Dynamics, The Pennsylvania State University, University Park, PA, USA.
• Li Ge, Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, WI, USA.

Document Type

Article

Abstract

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.

Medical Subject Headings

Brain (diagnostic imaging, pathology); Cerebral Ventricles (diagnostic imaging, metabolism, pathology); Exome (genetics); Female; Genetic Predisposition to Disease; Humans; Hydrocephalus (cerebrospinal fluid, diagnostic imaging, genetics, pathology); Male; Mutation (genetics); Neural Stem Cells (metabolism, pathology); Neurogenesis (genetics); Neuroglia (metabolism, pathology); Transcription Factors (genetics); Tripartite Motif Proteins (genetics); Ubiquitin-Protein Ligases (genetics); Exome Sequencing

Publication Date

11-1-2020

Publication Title

Nature medicine

E-ISSN

1546-170X

Volume

26

Issue

11

First Page

1754

Last Page

1765

PubMed ID

33077954

Digital Object Identifier (DOI)

10.1038/s41591-020-1090-2

Recommended Citation

Jin, Sheng Chih; Dong, Weilai; Kundishora, Adam J.; Panchagnula, Shreyas; Moreno-De-Luca, Andres; Furey, Charuta G.; Allocco, August A.; Walker, Rebecca L.; Nelson-Williams, Carol; Smith, Hannah; Dunbar, Ashley; Conine, Sierra; Lu, Qiongshi; Zeng, Xue; Sierant, Michael C.; Knight, James R.; Sullivan, William; Duy, Phan Q.; DeSpenza, Tyrone; Reeves, Benjamin C.; Karimy, Jason K.; Marlier, Arnaud; Castaldi, Christopher; Tikhonova, Irina R.; Li, Boyang; Peña, Helena Perez; Broach, James R.; Kabachelor, Edith M.; Ssenyonga, Peter; Hehnly, Christine; and Ge, Li, "Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus" (2020). Neurosurgery. 2401.
https://scholar.barrowneuro.org/neurosurgery/2401