Unraveling haplotype errors in the DFNA33 locus

Barbara Vona; Sabrina Regele; Aboulfazl Rad; Nicola Strenzke; Justin A Pater; Katrin Neumann; Marc Sturm; Tobias B Haack; Antoinette G Am Zehnhoff-Dinnesen

doi:10.3389/fgene.2023.1214736

Unraveling haplotype errors in the DFNA33 locus

Front Genet. 2023 Aug 21:14:1214736. doi: 10.3389/fgene.2023.1214736. eCollection 2023.

Authors

Barbara Vona^{1

2

3}, Sabrina Regele⁴, Aboulfazl Rad¹, Nicola Strenzke⁵, Justin A Pater^{6

7}, Katrin Neumann⁴, Marc Sturm⁸, Tobias B Haack^{8

9}, Antoinette G Am Zehnhoff-Dinnesen⁴

Affiliations

¹ Tübingen Hearing Research Centre, Department of Otolaryngology, Head and Neck Surgery, Eberhard Karls University Tübingen, Tübingen, Germany.
² Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
³ Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.
⁴ Department of Phoniatrics and Pedaudiology, University Hospital Münster, University of Münster, Münster, Germany.
⁵ Auditory Systems Physiology Group, Department of Otolaryngology and Institute for Auditory Neuroscience, University Medical Center Göttingen, Göttingen, Germany.
⁶ Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States.
⁷ Health Sciences Centre, Faculty of Medicine, Memorial University, St. John's, NL, Canada.
⁸ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
⁹ Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.

Abstract

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.

Keywords: ATP11A; DFNA33; genome sequencing; haplotype analysis; hereditary hearing loss; unresolved deafness loci.

Grants and funding

This work was supported by the Centers for Rare Diseases Tübingen, intramural funding (fortüne) at the University of Tübingen (2545-1-0 to BV), and the German Research Foundation (DFG) VO 2138/7-1 (BV, #469177153). Additional support from the DFG was provided via SFB 889 (Project A06 to NS) via the Heisenberg program (NS, #406266759) and the Multiscale Bioimaging Cluster of Excellence (MBExC).