loading page

Molecular characterization of pathogenic OTOA gene conversions in hearing loss patients
  • +11
  • Sacha Laurent,
  • Corinne Gehrig,
  • Thierry Nouspikel,
  • Sami S Amr,
  • Andrea Oza,
  • Elissa Murphy,
  • Anne Vannier,
  • Frédérique Sloan Béna,
  • Maria Teresa Carminho-Rodrigues,
  • Jean-Louis Blouin,
  • Hélène Cao Van,
  • Marc Abramowicz,
  • Ariane Paoloni-Giacobino,
  • Michel Guipponi
Sacha Laurent
Genetic Medecine Unit, Department of Diagnostic, University Hospitals of Geneva
Author Profile
Corinne Gehrig
Genetic Medecine Unit, Department of Diagnostic, University Hospitals of Geneva
Author Profile
Thierry Nouspikel
Genetic Medecine Unit, Department of Diagnostic, University Hospitals of Geneva
Author Profile
Sami S Amr
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, Massachusetts, USA
Author Profile
Andrea Oza
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, Massachusetts, USA
Author Profile
Elissa Murphy
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, Massachusetts, USA
Author Profile
Anne Vannier
Genetic Medecine Unit, Department of Diagnostic, University Hospitals of Geneva
Author Profile
Frédérique Sloan Béna
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland, Genetic Medecine Unit, Department of Diagnostic, University Hospitals of Geneva
Author Profile
Maria Teresa Carminho-Rodrigues
Genetic Medecine Unit, Department of Diagnostic, University Hospitals of Geneva
Author Profile
Jean-Louis Blouin
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland, Genetic Medecine Unit, Department of Diagnostic, University Hospitals of Geneva
Author Profile
Hélène Cao Van
Pediatric Otolaryngology Unit, Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals of Geneva, Geneva, Switzerland
Author Profile
Marc Abramowicz
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland, Genetic Medecine Unit, Department of Diagnostic, University Hospitals of Geneva
Author Profile
Ariane Paoloni-Giacobino
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland, Genetic Medecine Unit, Department of Diagnostic, University Hospitals of Geneva
Author Profile
Michel Guipponi
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland, Genetic Medecine Unit, Department of Diagnostic, University Hospitals of Geneva
Author Profile

Abstract

Bi-allelic loss-of-function variants of OTOA are a well-known cause of mild-to-moderate hearing loss. Whereas non-allelic homologous recombination-mediated deletions of the gene are well known, gene conversions to pseudogene OTOAP1 have been reported in the literature but never fully described nor their pathogenicity assessed. Here, we report two unrelated patients with mild-to-moderate hearing-loss, who were compound heterozygotes for a converted allele and a deletion of OTOA. The conversions were initially detected through sequencing depths anomalies at the OTOA locus after exome sequencing, then confirmed with long range PCRs. Both conversions lead to loss-of-function by introducing a premature stop codon in exon 22 (p.Glu787*). Using genomic alignments and long read nanopore sequencing, we found that the two probands carry converted alleles of widely different lengths, suggesting that they originated from different mechanisms of gene conversion.

Peer review status:Published

15 Sep 2020Submitted to Human Mutation
17 Sep 2020Submission Checks Completed
17 Sep 2020Assigned to Editor
29 Sep 2020Reviewer(s) Assigned
21 Oct 2020Review(s) Completed, Editorial Evaluation Pending
28 Oct 2020Editorial Decision: Revise Minor
06 Nov 20201st Revision Received
09 Nov 2020Assigned to Editor
09 Nov 2020Submission Checks Completed
09 Nov 2020Reviewer(s) Assigned
13 Nov 2020Review(s) Completed, Editorial Evaluation Pending
01 Dec 2020Editorial Decision: Revise Minor
02 Dec 20202nd Revision Received
03 Dec 2020Assigned to Editor
03 Dec 2020Submission Checks Completed
03 Dec 2020Review(s) Completed, Editorial Evaluation Pending
16 Dec 2020Editorial Decision: Accept
25 Jan 2021Published in Human Mutation. 10.1002/humu.24167