Format

Send to

Choose Destination
Neuron. 2018 Jul 25;99(2):302-314.e4. doi: 10.1016/j.neuron.2018.06.019. Epub 2018 Jul 5.

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

Author information

1
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.
2
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
3
Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
4
Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, WI 53706, USA.
5
Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
6
Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
7
Department of Neurological Surgery and Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.
8
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.
9
Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
10
Department of Neurological Surgery, University of Wisconsin Medical School, Madison, WI 53726, USA.
11
Department of Neurosurgery, University of Alabama School of Medicine, Birmingham, AL 35233, USA.
12
Yale Center for Genome Analysis, Yale University, New Haven, CT 06510, USA.
13
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Center for Genome Analysis, Yale University, New Haven, CT 06510, USA.
14
Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
15
Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, London WC1N 1AX, UK.
16
Kartal Dr. Lutfi Kirdar Research and Training Hospital, Istanbul 34860, Turkey.
17
Acibadem Mehmet Ali Aydinlar University, School of Medicine, Department of Neurosurgery, Division of Pediatric Neurosurgery, Istanbul 34752, Turkey.
18
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065, USA.
19
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; Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: kristopher.kahle@yale.edu.

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 × 10-7), SMARCC1 (p = 8.15 × 10-10), and PTCH1 (p = 1.06 × 10-6). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10-4). 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.

KEYWORDS:

PTCH1; SHH; SMARCC1; TRIM71; aqueductal stenosis; congenital hydrocephalus; de novo variants; gene discovery; neural stem cell; whole-exome sequencing

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center