Molecular characterization of pathogenic OTOA gene conversions in hearing loss patients

Abstract

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).

Benefits of Exome Sequencing in Children with Suspected Isolated Hearing Loss

“…Therefore, these genes share a high level of homology (>99%). In our patient, gene conversion occurred between the exon 20-21 of the OTOA gene replaced by exon 1 and 2 of the pseudogene OTPAP1 [33]. This gene conversion is expected to result in a premature stop codon that would either result in a truncated protein or an absence of protein through mRNA nonsense-mediated decay.…”

Utility of Whole Genome Sequencing for Population Screening of Deafness-Related Genetic Variants and Cytomegalovirus Infection in Newborns

“…OTOA encodes otoancorin, a protein that is important for conditioning proper stimulation of the inner hair cells (Zwaenepoel et al, 2002). It has 99% sequence similarity with exons 22-28 of the pseudogene OTOAP1, which generally leads to non-allelic homologous recombination-mediated deletions (Laurent et al, 2021). Considering the high prevalence of these two genes in hearing loss patients and the limitation of WGS, the residual risk should be calculated and the newborns' guardians should be informed prior to testing.…”

Compound Heterozygosity for OTOA Truncating Variant and Genomic Rearrangement Cause Autosomal Recessive Sensorineural Hearing Loss in an Italian Family

“…This rearrangement partly overlaps the 110 Kb microdeletion found by Laurent and coll. [ 13 ]. Microdeletions of OTOA are the second most common type of causative CNVs in hereditary HL [ 14 ] with a rate of less than 0.1–0.2% in the general population [ 15 ].…”

“…Therefore, it is expected that the number of causative alleles due to OTOA CNVs will increase in the future, thus supporting the clinical utility of bioinformatics pipelines including CNV analysis and/or integrative molecular dosage-sensitive investigations in hereditary HL. The presence of the OTOAP1 pseudogene prompted us to consider conversion as an alternative molecular mechanism leading to point variants in OTOA [ 13 ]. Concerning the c.2223G>A heterozygous variant in the maternal allele in this family, the mutated allele c.2223A is not present in the deposited sequence of OTOAP1 .…”