Mutation analysis of the SLC26A4, FOXI1 and KCNJ10 genes in individuals with congenital hearing loss
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Abstract
Pendred syndrome (PDS) and DFNB4 comprise a phenotypic spectrum of sensorineural hearing loss disorders that typically result from biallelic mutations of the SLC26A4 gene. Although PDS and DFNB4 are recessively inherited, sequencing of the coding regions and splice sites of SLC26A4 in individuals suspected to be affected with these conditions often fails to identify two mutations. We investigated the potential contribution of large SLC26A4 deletions and duplications to sensorineural hearing loss (SNHL) by screening 107 probands with one known SLC26A4 mutation by Multiplex Ligation-dependent Probe Amplification (MLPA). A heterozygous deletion, spanning exons 4-6, was detected in only one individual, accounting for approximately 1% of the missing mutations in our cohort. This low frequency is consistent with previously published MLPA results. We also examined the potential involvement of digenic inheritance in PDS/DFNB4 by sequencing the coding regions of FOXI1 and KCNJ10. Of the 29 probands who were sequenced, three carried nonsynonymous variants including one novel sequence change in FOXI1 and two polymorphisms in KCNJ10. We performed a review of prior studies and, in conjunction with our current data, conclude that the frequency of FOXI1 (1.4%) and KCNJ10 (3.6%) variants in PDS/DFNB4 individuals is low. Our results, in combination with previously published reports, indicate that large SLC26A4 deletions and duplications as well as mutations of FOXI1 and KCNJ10 play limited roles in the pathogenesis of SNHL and suggest that other genetic factors likely contribute to the phenotype.
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2014. Mutation analysis of the SLC26A4, FOXI1 and KCNJ10 genes in individuals with congenital hearing loss. PeerJ PrePrints 2:e275v1 https://doi.org/10.7287/peerj.preprints.275v1note This preprint is not peer-reviewed. You may wish to reference the subsequent peer-reviewed version of this article.
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Competing Interests
Colin J Davidson is an employee of Life Technologies.
Iris Schrijver serves as an Academic Editor for PeerJ.
Author Contributions
Lynn M Pique conceived and designed the experiments, performed the experiments, analyzed the data, wrote the paper, prepared figures and/or tables, reviewed drafts of the paper.
Marie-Luise Brennan analyzed the data, contributed reagents/materials/analysis tools, wrote the paper, prepared figures and/or tables, reviewed drafts of the paper.
Colin J Davidson performed the experiments, analyzed the data, contributed reagents/materials/analysis tools, reviewed drafts of the paper.
Frederick Schaefer contributed reagents/materials/analysis tools, reviewed drafts of the paper.
John Greinwald Jr. contributed reagents/materials/analysis tools, reviewed drafts of the paper.
Iris Schrijver conceived and designed the experiments, analyzed the data, contributed reagents/materials/analysis tools, wrote the paper, prepared figures and/or tables, reviewed drafts of the paper.
Human Ethics
The following information was supplied relating to ethical approvals (i.e., approving body and any reference numbers):
(1.) Stanford University Administrative Panels for the Protection of Human Subjects (2.) IRB Approval Numbers IRB-14011 and IRB-8353
Funding
Financial support for this work was provided by Stanford University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
