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

Authors

• Charuta Gavankar Furey, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
• Jungmin Choi, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
• Sheng Chih Jin, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
• Xue Zeng, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
• Andrew T. Timberlake, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
• Carol Nelson-Williams, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
• M Shahid Mansuri, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
• Qiongshi Lu, Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, WI 53706, USA.
• Daniel Duran, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
• Shreyas Panchagnula, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
• August Allocco, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
• Jason K. Karimy, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
• Arjun Khanna, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
• Jonathan R. Gaillard, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
• Tyrone DeSpenza, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
• Prince Antwi, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
• Erin Loring, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
• William E. Butler, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
• Edward R. Smith, Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
• Benjamin C. Warf, Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
• Jennifer M. Strahle, Department of Neurological Surgery and Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.
• David D. Limbrick, Department of Neurological Surgery and Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.
• Phillip B. Storm, Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
• Gregory Heuer, Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
• Eric M. Jackson, Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
• Bermans J. Iskandar, Department of Neurological Surgery, University of Wisconsin Medical School, Madison, WI 53726, USA.
• James M. Johnston, Department of Neurosurgery, University of Alabama School of Medicine, Birmingham, AL 35233, USA.
• Irina Tikhonova, Yale Center for Genome Analysis, Yale University, New Haven, CT 06510, USA.
• Christopher Castaldi, Yale Center for Genome Analysis, Yale University, New Haven, CT 06510, USA.
• Francesc López-Giráldez, Yale Center for Genome Analysis, Yale University, New Haven, CT 06510, USA.
• Robert D. Bjornson, Yale Center for Genome Analysis, Yale University, New Haven, CT 06510, USA.

Document Type

Article

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.

Medical Subject Headings

Cohort Studies; Exome (genetics); Female; Humans; Hydrocephalus (diagnosis, genetics); Male; Mutation (genetics); Neural Stem Cells (pathology, physiology); Patched-1 Receptor (genetics); Pedigree; Transcription Factors (genetics); Exome Sequencing (methods)

Publication Date

7-25-2018

Publication Title

Neuron

E-ISSN

1097-4199

Volume

99

Issue

2

First Page

302

Last Page

314.e4

PubMed ID

29983323

Digital Object Identifier (DOI)

10.1016/j.neuron.2018.06.019

Recommended Citation

Furey, Charuta Gavankar; Choi, Jungmin; Jin, Sheng Chih; Zeng, Xue; Timberlake, Andrew T.; Nelson-Williams, Carol; Mansuri, M Shahid; Lu, Qiongshi; Duran, Daniel; Panchagnula, Shreyas; Allocco, August; Karimy, Jason K.; Khanna, Arjun; Gaillard, Jonathan R.; DeSpenza, Tyrone; Antwi, Prince; Loring, Erin; Butler, William E.; Smith, Edward R.; Warf, Benjamin C.; Strahle, Jennifer M.; Limbrick, David D.; Storm, Phillip B.; Heuer, Gregory; Jackson, Eric M.; Iskandar, Bermans J.; Johnston, James M.; Tikhonova, Irina; Castaldi, Christopher; López-Giráldez, Francesc; and Bjornson, Robert D., "De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus" (2018). Neurosurgery. 2399.
https://scholar.barrowneuro.org/neurosurgery/2399