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Challenges and solutions for gene identification in the presence of familial locus heterogeneity

Next-generation sequencing (NGS) of exomes and genomes has accelerated the identification of genes involved in Mendelian phenotypes. However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25% for uncovering the pathological variant underlying...

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Autores principales: Rehman, Atteeq U, Santos-Cortez, Regie Lyn P, Drummond, Meghan C, Shahzad, Mohsin, Lee, Kwanghyuk, Morell, Robert J, Ansar, Muhammad, Jan, Abid, Wang, Xin, Aziz, Abdul, Riazuddin, Saima, Smith, Joshua D, Wang, Gao T, Ahmed, Zubair M, Gul, Khitab, Shearer, A Eliot, Smith, Richard J H, Shendure, Jay, Bamshad, Michael J, Nickerson, Deborah A, Hinnant, John, Khan, Shaheen N, Fisher, Rachel A, Ahmad, Wasim, Friderici, Karen H, Riazuddin, Sheikh, Friedman, Thomas B, Wilch, Ellen S, Leal, Suzanne M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538203/
https://www.ncbi.nlm.nih.gov/pubmed/25491636
http://dx.doi.org/10.1038/ejhg.2014.266
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author Rehman, Atteeq U
Santos-Cortez, Regie Lyn P
Drummond, Meghan C
Shahzad, Mohsin
Lee, Kwanghyuk
Morell, Robert J
Ansar, Muhammad
Jan, Abid
Wang, Xin
Aziz, Abdul
Riazuddin, Saima
Smith, Joshua D
Wang, Gao T
Ahmed, Zubair M
Gul, Khitab
Shearer, A Eliot
Smith, Richard J H
Shendure, Jay
Bamshad, Michael J
Nickerson, Deborah A
Hinnant, John
Khan, Shaheen N
Fisher, Rachel A
Ahmad, Wasim
Friderici, Karen H
Riazuddin, Sheikh
Friedman, Thomas B
Wilch, Ellen S
Leal, Suzanne M
author_facet Rehman, Atteeq U
Santos-Cortez, Regie Lyn P
Drummond, Meghan C
Shahzad, Mohsin
Lee, Kwanghyuk
Morell, Robert J
Ansar, Muhammad
Jan, Abid
Wang, Xin
Aziz, Abdul
Riazuddin, Saima
Smith, Joshua D
Wang, Gao T
Ahmed, Zubair M
Gul, Khitab
Shearer, A Eliot
Smith, Richard J H
Shendure, Jay
Bamshad, Michael J
Nickerson, Deborah A
Hinnant, John
Khan, Shaheen N
Fisher, Rachel A
Ahmad, Wasim
Friderici, Karen H
Riazuddin, Sheikh
Friedman, Thomas B
Wilch, Ellen S
Leal, Suzanne M
author_sort Rehman, Atteeq U
collection PubMed
description Next-generation sequencing (NGS) of exomes and genomes has accelerated the identification of genes involved in Mendelian phenotypes. However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25% for uncovering the pathological variant underlying disease etiology. An important reason for such failures is familial locus heterogeneity, where within a single pedigree causal variants in two or more genes underlie Mendelian trait etiology. As examples of intra- and inter-sibship familial locus heterogeneity, we present 10 consanguineous Pakistani families segregating hearing impairment due to homozygous variants in two different hearing impairment genes and a European-American pedigree in which hearing impairment is caused by four variants in three different genes. We have identified 41 additional pedigrees with syndromic and nonsyndromic hearing impairment for which a single previously reported hearing impairment gene has been identified but only segregates with the phenotype in a subset of affected pedigree members. We estimate that locus heterogeneity occurs in 15.3% (95% confidence interval: 11.9%, 19.9%) of the families in our collection. We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data. Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification.
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spelling pubmed-45382032015-08-21 Challenges and solutions for gene identification in the presence of familial locus heterogeneity Rehman, Atteeq U Santos-Cortez, Regie Lyn P Drummond, Meghan C Shahzad, Mohsin Lee, Kwanghyuk Morell, Robert J Ansar, Muhammad Jan, Abid Wang, Xin Aziz, Abdul Riazuddin, Saima Smith, Joshua D Wang, Gao T Ahmed, Zubair M Gul, Khitab Shearer, A Eliot Smith, Richard J H Shendure, Jay Bamshad, Michael J Nickerson, Deborah A Hinnant, John Khan, Shaheen N Fisher, Rachel A Ahmad, Wasim Friderici, Karen H Riazuddin, Sheikh Friedman, Thomas B Wilch, Ellen S Leal, Suzanne M Eur J Hum Genet Article Next-generation sequencing (NGS) of exomes and genomes has accelerated the identification of genes involved in Mendelian phenotypes. However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25% for uncovering the pathological variant underlying disease etiology. An important reason for such failures is familial locus heterogeneity, where within a single pedigree causal variants in two or more genes underlie Mendelian trait etiology. As examples of intra- and inter-sibship familial locus heterogeneity, we present 10 consanguineous Pakistani families segregating hearing impairment due to homozygous variants in two different hearing impairment genes and a European-American pedigree in which hearing impairment is caused by four variants in three different genes. We have identified 41 additional pedigrees with syndromic and nonsyndromic hearing impairment for which a single previously reported hearing impairment gene has been identified but only segregates with the phenotype in a subset of affected pedigree members. We estimate that locus heterogeneity occurs in 15.3% (95% confidence interval: 11.9%, 19.9%) of the families in our collection. We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data. Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification. Nature Publishing Group 2015-09 2014-12-10 /pmc/articles/PMC4538203/ /pubmed/25491636 http://dx.doi.org/10.1038/ejhg.2014.266 Text en Copyright © 2015 Macmillan Publishers Limited
spellingShingle Article
Rehman, Atteeq U
Santos-Cortez, Regie Lyn P
Drummond, Meghan C
Shahzad, Mohsin
Lee, Kwanghyuk
Morell, Robert J
Ansar, Muhammad
Jan, Abid
Wang, Xin
Aziz, Abdul
Riazuddin, Saima
Smith, Joshua D
Wang, Gao T
Ahmed, Zubair M
Gul, Khitab
Shearer, A Eliot
Smith, Richard J H
Shendure, Jay
Bamshad, Michael J
Nickerson, Deborah A
Hinnant, John
Khan, Shaheen N
Fisher, Rachel A
Ahmad, Wasim
Friderici, Karen H
Riazuddin, Sheikh
Friedman, Thomas B
Wilch, Ellen S
Leal, Suzanne M
Challenges and solutions for gene identification in the presence of familial locus heterogeneity
title Challenges and solutions for gene identification in the presence of familial locus heterogeneity
title_full Challenges and solutions for gene identification in the presence of familial locus heterogeneity
title_fullStr Challenges and solutions for gene identification in the presence of familial locus heterogeneity
title_full_unstemmed Challenges and solutions for gene identification in the presence of familial locus heterogeneity
title_short Challenges and solutions for gene identification in the presence of familial locus heterogeneity
title_sort challenges and solutions for gene identification in the presence of familial locus heterogeneity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538203/
https://www.ncbi.nlm.nih.gov/pubmed/25491636
http://dx.doi.org/10.1038/ejhg.2014.266
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