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

Atteeq U. Rehman, Regie Lyn P. Santos-Cortez, Meghan C. Drummond, Mohsin Shahzad, Kwanghyuk Lee, Robert J. Morell, Muhammad Ansar, Abid Jan, Xin Wang, Abdul Aziz, Saima Riazuddin, Joshua D. Smith, Gao T. Wang, Zubair M. Ahmed, Khitab Gul, A. Eliot Shearer, Richard J.H. Smith, Jay Shendure, Michael J. Bamshad, Deborah A. NickersonJohn Hinnant, Shaheen N. Khan, Rachel A. Fisher, Wasim Ahmad, Karen H. Friderici, Sheikh Riazuddin, Thomas B. Friedman, Ellen S. Wilch, Suzanne M. Leal, Peter Anderson, Marcus Annable, Mallory Beightol, Brian L. Browning, Kati J. Buckingham, Christina Chen, Jennifer Chin, Jessica X. Chong, Colleen Davis, Lindsay Felker, Christopher Frazar, David Hanna, Gail P. Jarvik, Eric Johanson, Martin Kircher, Tom Kolar, Daniel Luksic, Margaret J. McMillin, Sean McGee, Brenton Munson, Brian J. O'Roak, Bryan Paeper, Karynne Patterson, Eric Phillips, Jessica Pijoan, Christa Poel, Peggy D. Robertson, Tristan Shaffer, Cindy Shephard, Deborah L. Siegel, Jeffrey C. Staples, Holly K. Tabor, Monica Tackett, Qian Yi, Zongxiao He, Gonçalo R. Abecasis, Goo Jun, Gregory M. Cooper, Preti Jain

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1207-1215
Number of pages9
JournalEuropean Journal of Human Genetics
Issue number9
StatePublished - Sep 14 2015
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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