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Neuron. 2015 Nov 4;88(3):499-513. doi: 10.1016/j.neuron.2015.09.048.

Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
3
Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
4
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
5
Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA.
6
Center for Human Genetics, University Hospitals Leuven, Herestraat, 49 B 3000 Leuven, Belgium.
7
Department of Child Neurology, Gaziantep Children's Hospital, Gaziantep 27560, Turkey.
8
Department of Medical Genetics, Bezmialem University, Istanbul 34093, Turkey.
9
Department of Medical Genetics, Numune Training and Research Hospital, Adana 01240, Turkey.
10
Department of Medical Genetics, Mersin University, Mersin 33343, Turkey.
11
Department of Medical Genetics, Medical Faculty of Eskisehir Osmangazi University, Eskisehir 26480, Turkey.
12
Department of Medical Genetics, Medical Faculty of Namik Kemal University, Tekirdag 59100, Turkey.
13
Department of Medical Genetics, Sami Ulus Children's Hospital, Ankara 06080, Turkey.
14
Department of Pediatric Neurology, Sami Ulus Children's Hospital, Ankara 06080, Turkey.
15
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
16
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
17
Department of Medical Genetics, Marmara University School of Medicine, Istanbul 34722, Turkey.
18
Department of Medical Genetics, Samsun Education and Research Hospital, Samsun 55100, Turkey.
19
Department of Medical Genetics, Gulhane Military Medical School, Ankara 06010, Turkey.
20
Department of Medical Genetics, Ege University Faculty of Medicine, Izmir 35040, Turkey.
21
Department of Medical Genetics, Zekai Tahir Burak Women's Health Training and Research Hospital, Ankara 06230, Turkey.
22
Medical Genetics Section, Balikesir Ataturk Public Hospital, Balikesir 10100, Turkey.
23
Department of Medical Genetics, Karadeniz Technical University, Trabzon 61310, Turkey.
24
Medical Genetics Section, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul 34303, Turkey.
25
Department of Medical Genetics, Dicle University Faculty of Medicine, Diyarbakir 21280, Turkey.
26
Medical Genetics Section, Konya Numune Training and Research Hospital, Konya 42250, Turkey.
27
Intergen Genetic Center, Ankara 06700, Turkey.
28
Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul 34098, Turkey.
29
Department of Pediatric Endocrinology and Diabetes, Marmara University Hospital, Istanbul 34899, Turkey.
30
Department of Pediatric Genetics, Marmara University Medical Faculty, Istanbul 34854, Turkey.
31
Department of Genetics, Necmettin Erbakan University, Meram Medical Faculty, Konya 42060, Turkey.
32
Damagen Genetic Diagnostic Center and Department of Medical Genetics, Hacettepe University Medical School, Ankara 06230, Turkey.
33
Department of Medical Genetics, Uludag University Medical Faculty, Bursa 16120, Turkey.
34
Biruni University, Istanbul 34010, Turkey.
35
Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA.
36
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
37
Department of Pediatrics and Medicine, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY 10032, USA.
38
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.

Abstract

Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.

PMID:
26539891
PMCID:
PMC4824012
DOI:
10.1016/j.neuron.2015.09.048
[Indexed for MEDLINE]
Free PMC Article

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