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

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dc.contributor.authorKaraca, Ender
dc.contributor.authorHarel, Tamar
dc.contributor.authorPehlivan, Davut
dc.contributor.authorJhangiani, Shalini N.
dc.contributor.authorGambin, Tomasz
dc.contributor.authorAkdemir, Zeynep Coban
dc.contributor.authorGonzaga-Jauregui, Claudia
dc.date.accessioned2024-02-23T14:13:20Z
dc.date.available2024-02-23T14:13:20Z
dc.date.issued2015
dc.departmentNEÜen_US
dc.description.abstractDevelopment 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.en_US
dc.description.sponsorshipU.S. National Human Genome Research Institute (NHGRI) NHLBI grant [U54HG006542]; NINDS [RO1 NS058529, K23NS078056]; NHGRI [5U54HG003273]; Medical Genetics Research Fellowship Program [T32 GM07526]; Regeneronen_US
dc.description.sponsorshipWe thank all the family members and collaborators who participated in this study. This work was supported by U.S. National Human Genome Research Institute (NHGRI) NHLBI grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, NINDS grant RO1 NS058529 to J. R. L., and NHGRI 5U54HG003273 to R. A. G. T. H. is supported by the Medical Genetics Research Fellowship Program (T32 GM07526). W. W. is supported by Career Development Award K23NS078056 from NINDS. The authors would like to thank the ExAC and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about. J.R.L. has stock ownership in 23andMe and Lasergen and is a paid consultant for Regeneron. J. R. L. is also a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the Medical Genetics Laboratory (https://www.bcm.edu/geneticlabs/). W. K. C. is a paid consultant for Regeneron and BioReference Laboratories. C.G.-J. and J. D. O. are employees of the RGC.en_US
dc.identifier.doi10.1016/j.neuron.2015.09.048
dc.identifier.endpage513en_US
dc.identifier.issn0896-6273
dc.identifier.issn1097-4199
dc.identifier.issue3en_US
dc.identifier.pmid26539891en_US
dc.identifier.scopus2-s2.0-84946140195en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage499en_US
dc.identifier.urihttps://doi.org/10.1016/j.neuron.2015.09.048
dc.identifier.urihttps://hdl.handle.net/20.500.12452/12391
dc.identifier.volume88en_US
dc.identifier.wosWOS:000365765400011en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherCell Pressen_US
dc.relation.ispartofNeuronen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[Keyword Not Available]en_US
dc.titleGenes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Diseaseen_US
dc.typeArticleen_US

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