Abstract
Hereditary hearing impairment is a common sensory disorder that is genetically and phenotypically heterogeneous. In this study, we used a homozygosity mapping and exome sequencing strategy to study a consanguineous Pakistani family with autosomal recessive severe-to-profound hearing impairment. This led to the identification of a missense variant (p.Ile369Thr) in the LMX1A gene affecting a conserved residue in the C-terminus of the protein, which was predicted damaging by an in silico bioinformatics analysis. The p.Ile369Thr variant disrupts several C-terminal and homeodomain residue interactions, including an interaction with homeodomain residue p.Val241 that was previously found to be involved in autosomal dominant progressive HI. LIM-homeodomain factor Lmx1a is expressed in the inner ear through development, shows a progressive restriction to non-sensory epithelia, and is important in the separation of the sensory and non-sensory domains in the inner ear. Homozygous Lmx1a mutant mice (Dreher) are deaf with dysmorphic ears with an abnormal morphogenesis and fused and misshapen sensory organs; however, computed tomography performed on a hearing-impaired family member did not reveal any cochleovestibular malformations. Our results suggest that LMX1A is involved in both human autosomal recessive and dominant sensorineural hearing impairment.
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Acknowledgements
This work was supported by the Higher Education Commission of Pakistan (to WA) and the National Institute on Deafness and Other Communication Disorders grants R01 DC011651 and R01 DC003594 (to SML). Exome sequencing was funded by the National Human Genome Research Institute and the National Heart, Lung and Blood Institute grant HG006493 (to DAN, MJB, and SML). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268201200008I. We would like to acknowledge the entire University of Washington Center for Mendelian Genomics team and their members for exome sequencing and bioinformatics support: Michael J. Bamshad (University of Washington, Seattle Children’s Hospital), Suzanne M. Leal (Baylor College of Medicine), and Deborah A. Nickerson (University of Washington); Peter Anderson (University of Washington), Marcus Annable (University of Washington), Elizabeth E. Blue (University of Washington), Kati J. Buckingham (University of Washington), Imen Chakchouk (Baylor College of Medicine), Jennifer Chin (University of Washington), Jessica X Chong (University of Washington), Rodolfo Cornejo Jr. (University of Washington), Colleen P. Davis (University of Washington), Christopher Frazar (University of Washington), Martha Horike-Pyne (University of Washington), Gail P. Jarvik (University of Washington), Eric Johanson (University of Washington), Ashley N. Kang (University of Washington), Tom Kolar (University of Washington), Stephanie A. Krauter (University of Washington), Colby T. Marvin (University of Washington), Sean McGee (University of Washington), Daniel J. McGoldrick (University of Washington), Karynne Patterson (University of Washington), Sam W. Phillips (University of Washington), Jessica Pijoan (University of Washington), Matthew A. Richardson (University of Washington), Peggy D. Robertson (University of Washington), Isabelle Schrauwen (Baylor College of Medicine), Krystal Slattery (University of Washington), Kathryn M. Shively (University of Washington), Joshua D. Smith (University of Washington), Monica Tackett (University of Washington), Alice E. Tattersall (University of Washington), Marc Wegener (University of Washington), Jeffrey M. Weiss (University of Washington), Marsha M. Wheeler (University of Washington), Qian Yi (University of Washington), and Di Zhang (Baylor College of Medicine).
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ANNOVAR and dbNSFP annotations of the variant in LMX1A and all additional rare variants of unknown significance identified by exome sequencing in individual IV:2 (XLSX 16 KB)
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Schrauwen, I., Chakchouk, I., Liaqat, K. et al. A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment. Hum Genet 137, 471–478 (2018). https://doi.org/10.1007/s00439-018-1899-7
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DOI: https://doi.org/10.1007/s00439-018-1899-7