Molecular characterization of pathogenic OTOA gene conversions in hearing loss patients.
Sacha LaurentCorinne GehrigThierry NouspikelSami S AmrAndrea M OzaElissa MurphyAnne VannierFrédérique Sloan BénaMaria Teresa Carminho-RodriguesJean-Louis BlouinHélène Cao VanMarc AbramowiczAriane Paoloni-GiacobinoMichel GuipponiPublished in: Human mutation (2021)
Bi-allelic loss-of-function variants of OTOA are a well-known cause of moderate-to-severe 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 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 polymerase chain reactions. 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 stretches of converted DNA of widely different lengths (at least 9 kbp and around 900 bp, respectively).
Keyphrases
- hearing loss
- copy number
- genome wide
- single cell
- single molecule
- end stage renal disease
- dna damage
- chronic kidney disease
- systematic review
- ejection fraction
- dna repair
- genome wide identification
- dna methylation
- gene expression
- early onset
- peritoneal dialysis
- cystic fibrosis
- pseudomonas aeruginosa
- cord blood
- staphylococcus aureus