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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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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. |
format | Online Article Text |
id | pubmed-4538203 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
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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