Unraveling haplotype errors in the DFNA33 locus

Frontiers in Genetics

Genetics

Nicola Strenzke¹  Justin A. Pater²  Antoinette G. Am Zehnhoff-Dinnesen³  Sabrina Regele³  Katrin Neumann³  Marc Sturm⁴  Tobias B. Haack⁵  Aboulfazl Rad⁶  Barbara Vona⁷ 

[1] Auditory Systems Physiology Group, Department of Otolaryngology and Institute for Auditory Neuroscience, University Medical Center Göttingen, Göttingen, Germany;Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States;Health Sciences Centre, Faculty of Medicine, Memorial University, St. John’s, NL, Canada;Department of Phoniatrics and Pedaudiology, University Hospital Münster, University of Münster, Münster, Germany;Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany;Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany;Centre for Rare Diseases, University of Tübingen, Tübingen, Germany;Tübingen Hearing Research Centre, Department of Otolaryngology, Head and Neck Surgery, Eberhard Karls University Tübingen, Tübingen, Germany;Tübingen Hearing Research Centre, Department of Otolaryngology, Head and Neck Surgery, Eberhard Karls University Tübingen, Tübingen, Germany;Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany;Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany;

关键词: ATP11A;    DFNA33;    genome sequencing;    haplotype analysis;    hereditary hearing loss;    unresolved deafness loci;   

DOI  :  10.3389/fgene.2023.1214736

 received in 2023-05-02, accepted in 2023-08-04,  发布年份 2023

来源: Frontiers

【 摘 要 】

Genetic heterogeneity makes it difficult to identify the causal genes for hearing loss. Studies from previous decades have mapped numerous genetic loci, providing critical supporting evidence for gene discovery studies. Despite widespread sequencing accessibility, many historically mapped loci remain without a causal gene. The DFNA33 locus was mapped in 2009 and coincidentally contains ATP11A, a gene recently associated with autosomal dominant hearing loss and auditory neuropathy type 2. In a rare opportunity, we genome-sequenced a member of the original family to determine whether the DFNA33 locus may also be assigned to ATP11A. We identified a deep intronic variant in ATP11A that showed evidence of functionally normal splicing. Furthermore, we re-assessed haplotypes from the originally published DFNA33 family and identified two double recombination events and one triple recombination event in the pedigree, a highly unlikely occurrence, especially at this scale. This brief research report also serves as a call to the community to revisit families who have previously been involved in gene mapping studies, provide closure, and resolve these historical loci.

【 授权许可】

Unknown   
Copyright © 2023 Vona, Regele, Rad, Strenzke, Pater, Neumann, Sturm, Haack and Am Zehnhoff-Dinnesen.