Severe or Profound Sensorineural Hearing Loss Caused by Novel <i>USH2A</i> Variants in Korea: Potential Genotype-Phenotype Correlation

Abstract

Objectives. We, herein, report two novel &lt;i&gt;USH2A&lt;/i&gt; variants from two unrelated Korean families and their clinical phenotypes, with attention to severe or more than severe sensorineural hearing loss (SNHL).Methods. Two postlingually deafened subjects (SB237-461, M/46 and SB354-692, F/34) with more than severe SNHL and also with suspicion of Usher syndrome type II (USH2) were enrolled. A comprehensive audiological and ophthalmological assessments were evaluated. We conducted the whole exome sequencing and subsequent pathogenicity prediction analysis.Results. We identified the following variants of &lt;i&gt;USH2A&lt;/i&gt; from the two probands manifesting more than severe SNHL and retinitis pigmentosa (RP): compound heterozygosity for a nonsense (c.8176C&gt;T: p.R2723X) and a missense variant (c.1823G&gt;A: p.C608Y) in SB237, and compound heterozygosity for two frameshift variants (c.14835delT: p.S4945fs &amp; c.13112_13115delAAAT: p.G4371fs) in SB354. Based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, two novel variants, c.1823G&gt;A: p.C608Y and c.14835delT: p.Ser4945fs, can be classified as “uncertain significance” and “pathogenic,” respectively. The audiogram exhibited more than severe SNHL and a down-sloping configuration, necessitating cochlear implantation. The ophthalmic examinations revealed typical features of RP. Interestingly, one proband (SB 354-692) carrying two truncating compound heterozygous variants exhibited more severe hearing loss than the other proband (SB 237-461), carrying one truncation with one missense variant.Conclusion. Our results provide insight on the expansion of audiological spectrum encompassing more than severe SNHL in Korean subjects harboring &lt;i&gt;USH2A&lt;/i&gt; variants, suggesting that &lt;i&gt;USH2A&lt;/i&gt; should also be included in the candidate gene of cochlear implantation. A specific combination of &lt;i&gt;USH2A&lt;/i&gt; variants causing truncating proteins in both alleles could demonstrate more severe audiological phenotype than that of &lt;i&gt;USH2A&lt;/i&gt; variants carrying one truncating mutation and one missense mutation, suggesting a possible genotype-phenotype correlation. The understanding of audiological complexity associated with &lt;i&gt;USH2A&lt;/i&gt; will be helpful for genetic counseling and treatment starategy.

Truncating Variants Contribute to Hearing Loss and Severe Retinopathy in USH2A-Associated Retinitis Pigmentosa in Japanese Patients

“…In previous studies, USH2A is a frequent causal gene in Japanese RP patients as well as Caucasian RP patients, yet the mutation spectrum is different among different ethnic groups [ 19 , 20 ]. Genotype–phenotype correlation in USH2A has been reported where truncating variants are associated with more severe visual and hearing impairments [ 9 , 21 , 22 ], and similar trends have also been reported in Asians [ 23 , 24 ]. In contrast, there are studies reporting that the differences in phenotypes are not clear in syndromic and non-syndromic or truncating variants and non-truncating variants [ 25 , 26 ].…”

Central auditory maturation and behavioral outcomes after cochlear implantation in prelingual auditory neuropathy spectrum disorder related to OTOF variants (DFNB9): Lessons from pilot study

“…The OTOF variants (Glu841Lys, Arg1856Trp, Leu1011Pro, Tyr1064Ter, and Arg1939Gln) were highly prevalent among Korean subjects with prelingual ANSD [ 6 , 20 , 24 ]. Subsequently, exome sequencing was performed to verify that the subjects did not carry convincing variants in the deafness panel, followed by bioinformatics analyses, as described previously [ 25 , 26 ]. The resulting readings were compared to the UCSC hg19 reference genome, and non-synonymous SNPs were filtered with a depth = 40; dbSNP138 was filtered out, except for the flagged SNP.…”

“…The resulting readings were compared to the UCSC hg19 reference genome, and non-synonymous SNPs were filtered with a depth = 40; dbSNP138 was filtered out, except for the flagged SNP. Using a comprehensive filtering process, rare single-nucleotide variations, indels, or splice-site variants were chosen, as described in our previous studies [ 25 , 26 ]. Subsequently, Sanger sequencing and segregation analyses were used to confirm the variant of the candidate deafness genes.…”

Novel genotype–phenotype correlation of functionally characterized LMX1A variants linked to sensorineural hearing loss

“…Raw data generated by ES were mapped onto the UCSC hg19 reference genome, and rare single‐nucleotide variations, indels, or splice‐site variants were selected. Filtration was used to identify the candidate variants, as previously described (Lee et al, 2020). The analytical approach applied in the study, as well as the number of candidate variants filtered at each step, is described in Figure S1.…”