Journal article
Challenges and solutions for gene identification in the presence of familial locus heterogeneity
European journal of human genetics : EJHG, Vol.23(9), pp.1207-1215
09/2015
DOI: 10.1038/ejhg.2014.266
PMCID: PMC4538203
PMID: 25491636
Abstract
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.
Details
- Title: Subtitle
- Challenges and solutions for gene identification in the presence of familial locus heterogeneity
- Creators
- Atteeq U Rehman - Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USARegie Lyn P Santos-Cortez - Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USAMeghan C Drummond - Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USAMohsin Shahzad - 1] National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USAKwanghyuk Lee - Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USARobert J Morell - Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USAMuhammad Ansar - 1] Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, PakistanAbid Jan - Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, PakistanXin Wang - Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USAAbdul Aziz - Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, PakistanSaima Riazuddin - 1] National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USAJoshua D Smith - Department of Genome Sciences, University of Washington, Seattle, WA, USAGao T Wang - Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USAZubair M Ahmed - Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USAKhitab Gul - National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, PakistanA Eliot Shearer - Molecular Otolaryngology and Renal Research Labs, Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA, USARichard J H Smith - Molecular Otolaryngology and Renal Research Labs, Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA, USAJay Shendure - Department of Genome Sciences, University of Washington, Seattle, WA, USAMichael J Bamshad - Department of Genome Sciences, University of Washington, Seattle, WA, USADeborah A Nickerson - Department of Genome Sciences, University of Washington, Seattle, WA, USAJohn Hinnant - Department of Religious Studies, Michigan State University, East Lansing, MI, USAShaheen N Khan - National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, PakistanRachel A Fisher - Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI, USAWasim Ahmad - Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, PakistanKaren H Friderici - 1] Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USAThomas B Friedman - Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USAEllen S Wilch - Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USASuzanne M Leal - Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USASheikh RiazuddinUniversity of Washington Center for Mendelian Genomics
- Resource Type
- Journal article
- Publication Details
- European journal of human genetics : EJHG, Vol.23(9), pp.1207-1215
- DOI
- 10.1038/ejhg.2014.266
- PMID
- 25491636
- PMCID
- PMC4538203
- NLM abbreviation
- Eur J Hum Genet
- ISSN
- 1018-4813
- eISSN
- 1476-5438
- Publisher
- England
- Grant note
- R01 DC011803 / NIDCD NIH HHS U54 HG006493 / NHGRI NIH HHS T32 DC000039 / NIDCD NIH HHS T32 GM007337 / NIGMS NIH HHS R01 DC012564 / NIDCD NIH HHS N01HG65403 / NHGRI NIH HHS R01 DC003544 / NIDCD NIH HHS UM1 HG006493 / NHGRI NIH HHS Z01 DC000039 / Intramural NIH HHS R01 DC011748 / NIDCD NIH HHS R01 DC003594 / NIDCD NIH HHS R01 DC011651 / NIDCD NIH HHS DC000039-18 / NIDCD NIH HHS R03 DC012434 / NIDCD NIH HHS
- Language
- English
- Date published
- 09/2015
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984006364502771
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