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Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate
BACKGROUND: Neurodevelopment is orchestrated by a wide range of genes, and the genetic causes of neurodevelopmental disorders are thus heterogeneous. We applied whole exome sequencing (WES) for molecular diagnosis and in silico analysis to identify novel disease gene candidates in a cohort from Saud...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950750/ https://www.ncbi.nlm.nih.gov/pubmed/27435318 http://dx.doi.org/10.1186/s12920-016-0208-3 |
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author | Charng, Wu-Lin Karaca, Ender Coban Akdemir, Zeynep Gambin, Tomasz Atik, Mehmed M. Gu, Shen Posey, Jennifer E. Jhangiani, Shalini N. Muzny, Donna M. Doddapaneni, Harsha Hu, Jianhong Boerwinkle, Eric Gibbs, Richard A. Rosenfeld, Jill A. Cui, Hong Xia, Fan Manickam, Kandamurugu Yang, Yaping Faqeih, Eissa A. Al Asmari, Ali Saleh, Mohammed A. M. El-Hattab, Ayman W. Lupski, James R. |
author_facet | Charng, Wu-Lin Karaca, Ender Coban Akdemir, Zeynep Gambin, Tomasz Atik, Mehmed M. Gu, Shen Posey, Jennifer E. Jhangiani, Shalini N. Muzny, Donna M. Doddapaneni, Harsha Hu, Jianhong Boerwinkle, Eric Gibbs, Richard A. Rosenfeld, Jill A. Cui, Hong Xia, Fan Manickam, Kandamurugu Yang, Yaping Faqeih, Eissa A. Al Asmari, Ali Saleh, Mohammed A. M. El-Hattab, Ayman W. Lupski, James R. |
author_sort | Charng, Wu-Lin |
collection | PubMed |
description | BACKGROUND: Neurodevelopment is orchestrated by a wide range of genes, and the genetic causes of neurodevelopmental disorders are thus heterogeneous. We applied whole exome sequencing (WES) for molecular diagnosis and in silico analysis to identify novel disease gene candidates in a cohort from Saudi Arabia with primarily Mendelian neurologic diseases. METHODS: We performed WES in 31 mostly consanguineous Arab families and analyzed both single nucleotide and copy number variants (CNVs) from WES data. Interaction/expression network and pathway analyses, as well as paralog studies were utilized to investigate potential pathogenicity and disease association of novel candidate genes. Additional cases for candidate genes were identified through the clinical WES database at Baylor Miraca Genetics Laboratories and GeneMatcher. RESULTS: We found known pathogenic or novel variants in known disease genes with phenotypic expansion in 6 families, disease-associated CNVs in 2 families, and 12 novel disease gene candidates in 11 families, including KIF5B, GRM7, FOXP4, MLLT1, and KDM2B. Overall, a potential molecular diagnosis was provided by variants in known disease genes in 17 families (54.8 %) and by novel candidate disease genes in an additional 11 families, making the potential molecular diagnostic rate ~90 %. CONCLUSIONS: Molecular diagnostic rate from WES is improved by exome-predicted CNVs. Novel candidate disease gene discovery is facilitated by paralog studies and through the use of informatics tools and available databases to identify additional evidence for pathogenicity. TRIAL REGISTRATION: Not applicable. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12920-016-0208-3) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4950750 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-49507502016-07-20 Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate Charng, Wu-Lin Karaca, Ender Coban Akdemir, Zeynep Gambin, Tomasz Atik, Mehmed M. Gu, Shen Posey, Jennifer E. Jhangiani, Shalini N. Muzny, Donna M. Doddapaneni, Harsha Hu, Jianhong Boerwinkle, Eric Gibbs, Richard A. Rosenfeld, Jill A. Cui, Hong Xia, Fan Manickam, Kandamurugu Yang, Yaping Faqeih, Eissa A. Al Asmari, Ali Saleh, Mohammed A. M. El-Hattab, Ayman W. Lupski, James R. BMC Med Genomics Research Article BACKGROUND: Neurodevelopment is orchestrated by a wide range of genes, and the genetic causes of neurodevelopmental disorders are thus heterogeneous. We applied whole exome sequencing (WES) for molecular diagnosis and in silico analysis to identify novel disease gene candidates in a cohort from Saudi Arabia with primarily Mendelian neurologic diseases. METHODS: We performed WES in 31 mostly consanguineous Arab families and analyzed both single nucleotide and copy number variants (CNVs) from WES data. Interaction/expression network and pathway analyses, as well as paralog studies were utilized to investigate potential pathogenicity and disease association of novel candidate genes. Additional cases for candidate genes were identified through the clinical WES database at Baylor Miraca Genetics Laboratories and GeneMatcher. RESULTS: We found known pathogenic or novel variants in known disease genes with phenotypic expansion in 6 families, disease-associated CNVs in 2 families, and 12 novel disease gene candidates in 11 families, including KIF5B, GRM7, FOXP4, MLLT1, and KDM2B. Overall, a potential molecular diagnosis was provided by variants in known disease genes in 17 families (54.8 %) and by novel candidate disease genes in an additional 11 families, making the potential molecular diagnostic rate ~90 %. CONCLUSIONS: Molecular diagnostic rate from WES is improved by exome-predicted CNVs. Novel candidate disease gene discovery is facilitated by paralog studies and through the use of informatics tools and available databases to identify additional evidence for pathogenicity. TRIAL REGISTRATION: Not applicable. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12920-016-0208-3) contains supplementary material, which is available to authorized users. BioMed Central 2016-07-19 /pmc/articles/PMC4950750/ /pubmed/27435318 http://dx.doi.org/10.1186/s12920-016-0208-3 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Charng, Wu-Lin Karaca, Ender Coban Akdemir, Zeynep Gambin, Tomasz Atik, Mehmed M. Gu, Shen Posey, Jennifer E. Jhangiani, Shalini N. Muzny, Donna M. Doddapaneni, Harsha Hu, Jianhong Boerwinkle, Eric Gibbs, Richard A. Rosenfeld, Jill A. Cui, Hong Xia, Fan Manickam, Kandamurugu Yang, Yaping Faqeih, Eissa A. Al Asmari, Ali Saleh, Mohammed A. M. El-Hattab, Ayman W. Lupski, James R. Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate |
title | Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate |
title_full | Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate |
title_fullStr | Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate |
title_full_unstemmed | Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate |
title_short | Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate |
title_sort | exome sequencing in mostly consanguineous arab families with neurologic disease provides a high potential molecular diagnosis rate |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950750/ https://www.ncbi.nlm.nih.gov/pubmed/27435318 http://dx.doi.org/10.1186/s12920-016-0208-3 |
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