title: Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ender
authors.initials: E
authors.lastname: Karaca
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Harel
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Davut
authors.initials: D
authors.lastname: Pehlivan
authors.affiliation: 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.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Coban Akdemir
authors.affiliation: Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.affiliation: 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.
authors.forename: Serkan
authors.initials: S
authors.lastname: Erdin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Bayram
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Campbell
authors.affiliation: Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Jill V
authors.initials: JV
authors.lastname: Hunter
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mehmed M
authors.initials: MM
authors.lastname: Atik
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, Herestraat, 49 B 3000 Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wiszniewski
authors.affiliation: Department of Child Neurology, Gaziantep Children's Hospital, Gaziantep 27560, Turkey.
authors.forename: Sedat
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authors.lastname: Isikay
authors.affiliation: Department of Medical Genetics, Bezmialem University, Istanbul 34093, Turkey.
authors.forename: Gozde
authors.initials: G
authors.lastname: Yesil
authors.affiliation: Department of Medical Genetics, Numune Training and Research Hospital, Adana 01240, Turkey.
authors.forename: Ozge O
authors.initials: OO
authors.lastname: Yuregir
authors.affiliation: Department of Medical Genetics, Mersin University, Mersin 33343, Turkey.
authors.forename: Sevcan
authors.initials: S
authors.lastname: Tug Bozdogan
authors.affiliation: Department of Medical Genetics, Medical Faculty of Eskisehir Osmangazi University, Eskisehir 26480, Turkey.
authors.forename: Huseyin
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authors.lastname: Aslan
authors.affiliation: Department of Medical Genetics, Medical Faculty of Namik Kemal University, Tekirdag 59100, Turkey.
authors.forename: Hatip
authors.initials: H
authors.lastname: Aydin
authors.affiliation: Department of Medical Genetics, Sami Ulus Children's Hospital, Ankara 06080, Turkey.
authors.forename: Tulay
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authors.lastname: Tos
authors.affiliation: Department of Pediatric Neurology, Sami Ulus Children's Hospital, Ankara 06080, Turkey.
authors.forename: Ayse
authors.initials: A
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authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: De Vivo
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Preti
authors.initials: P
authors.lastname: Jain
authors.affiliation: Department of Medical Genetics, Marmara University School of Medicine, Istanbul 34722, Turkey.
authors.forename: B Bilge
authors.initials: BB
authors.lastname: Geckinli
authors.affiliation: Department of Medical Genetics, Samsun Education and Research Hospital, Samsun 55100, Turkey.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Sezer
authors.affiliation: Department of Medical Genetics, Gulhane Military Medical School, Ankara 06010, Turkey.
authors.forename: Davut
authors.initials: D
authors.lastname: Gul
authors.affiliation: Department of Medical Genetics, Ege University Faculty of Medicine, Izmir 35040, Turkey.
authors.forename: Burak
authors.initials: B
authors.lastname: Durmaz
authors.affiliation: Department of Medical Genetics, Ege University Faculty of Medicine, Izmir 35040, Turkey.
authors.forename: Ozgur
authors.initials: O
authors.lastname: Cogulu
authors.affiliation: Department of Medical Genetics, Ege University Faculty of Medicine, Izmir 35040, Turkey.
authors.forename: Ferda
authors.initials: F
authors.lastname: Ozkinay
authors.affiliation: Department of Medical Genetics, Zekai Tahir Burak Women's Health Training and Research Hospital, Ankara 06230, Turkey.
authors.forename: Vehap
authors.initials: V
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authors.affiliation: Medical Genetics Section, Balikesir Ataturk Public Hospital, Balikesir 10100, Turkey.
authors.forename: Sukru
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authors.lastname: Candan
authors.affiliation: Department of Medical Genetics, Karadeniz Technical University, Trabzon 61310, Turkey.
authors.forename: Alper Han
authors.initials: AH
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authors.affiliation: Department of Medical Genetics, Karadeniz Technical University, Trabzon 61310, Turkey.
authors.forename: Mevlit
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authors.affiliation: Medical Genetics Section, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul 34303, Turkey.
authors.forename: Elif
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authors.lastname: Yilmaz Gulec
authors.affiliation: Medical Genetics Section, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul 34303, Turkey.
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authors.affiliation: Medical Genetics Section, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul 34303, Turkey.
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authors.affiliation: Medical Genetics Section, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul 34303, Turkey.
authors.forename: Fatma
authors.initials: F
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authors.affiliation: Department of Medical Genetics, Dicle University Faculty of Medicine, Diyarbakir 21280, Turkey.
authors.forename: Salih
authors.initials: S
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authors.affiliation: Medical Genetics Section, Konya Numune Training and Research Hospital, Konya 42250, Turkey.
authors.forename: Salih
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authors.lastname: Cicek
authors.affiliation: Intergen Genetic Center, Ankara 06700, Turkey.
authors.forename: Kadri
authors.initials: K
authors.lastname: Karaer
authors.affiliation: Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul 34098, Turkey.
authors.forename: Asuman
authors.initials: A
authors.lastname: Koparir
authors.affiliation: Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul 34098, Turkey.
authors.forename: Mehmet Bugrahan
authors.initials: MB
authors.lastname: Duz
authors.affiliation: Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul 34098, Turkey.
authors.forename: Emre
authors.initials: E
authors.lastname: Kirat
authors.affiliation: Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul 34098, Turkey.
authors.forename: Elif
authors.initials: E
authors.lastname: Fenercioglu
authors.affiliation: Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul 34098, Turkey.
authors.forename: Hakan
authors.initials: H
authors.lastname: Ulucan
authors.affiliation: Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul 34098, Turkey.
authors.forename: Mehmet
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authors.affiliation: Department of Pediatric Endocrinology and Diabetes, Marmara University Hospital, Istanbul 34899, Turkey.
authors.forename: Tulay
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authors.lastname: Guran
authors.affiliation: Department of Pediatric Genetics, Marmara University Medical Faculty, Istanbul 34854, Turkey.
authors.forename: Nursel
authors.initials: N
authors.lastname: Elcioglu
authors.affiliation: Department of Genetics, Necmettin Erbakan University, Meram Medical Faculty, Konya 42060, Turkey.
authors.forename: Mahmut Selman
authors.initials: MS
authors.lastname: Yildirim
authors.affiliation: Damagen Genetic Diagnostic Center and Department of Medical Genetics, Hacettepe University Medical School, Ankara 06230, Turkey.
authors.forename: Dilek
authors.initials: D
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authors.affiliation: Damagen Genetic Diagnostic Center and Department of Medical Genetics, Hacettepe University Medical School, Ankara 06230, Turkey.
authors.forename: Mehmet
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authors.affiliation: Department of Medical Genetics, Uludag University Medical Faculty, Bursa 16120, Turkey.
authors.forename: Mehmet
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authors.affiliation: Department of Medical Genetics, Uludag University Medical Faculty, Bursa 16120, Turkey.
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authors.affiliation: Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
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authors.initials: JD
authors.lastname: Overton
authors.affiliation: Biruni University, Istanbul 34010, Turkey.
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authors.affiliation: Biruni University, Istanbul 34010, Turkey.
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authors.affiliation: 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.
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authors.initials: DM
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authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA.
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authors.initials: DR
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authors.affiliation: 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.
authors.forename: Eric
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authors.affiliation: Department of Pediatrics and Medicine, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY 10032, USA.
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authors.initials: WK
authors.lastname: Chung
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: 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.
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authors.initials: JR
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mesh_terms: D001921:Brain / Q000002:abnormalities / Q000473:pathology*; D015331:Cohort Studies; D030541:Databases, Genetic; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics*; D056726:Genetic Association Studies / Q000379:methods; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis / Q000379:methods*; D009422:Nervous System Diseases / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree