Severe or Profound Sensorineural Hearing Loss Caused by Novel USH2A Variants in Korea: Potential Genotype-Phenotype Correlation
- Author:
Sang-Yeon LEE
1
;
Kwangsic JOO
;
Jayoung OH
;
Jin Hee HAN
;
Hye-Rim PARK
;
Seungmin LEE
;
Doo-Yi OH
;
Se Joon WOO
;
Byung Yoon CHOI
Author Information
- Publication Type:Original Article
- From:Clinical and Experimental Otorhinolaryngology 2020;13(2):113-122
- CountryRepublic of Korea
- Language:English
-
Abstract:
Objectives:. We, herein, report two novel USH2A 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 USH2A from the two probands manifesting more than severe SNHL and retinitis pigmentosa (RP): compound heterozygosity for a nonsense (c.8176C>T: p.R2723X) and a missense variant (c.1823G>A: p.C608Y) in SB237, and compound heterozygosity for two frameshift variants (c.14835delT: p.S4945fs & 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>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 USH2A variants, suggesting that USH2A should also be included in the candidate gene of cochlear implantation. A specific combination of USH2A variants causing truncating proteins in both alleles could demonstrate more severe audiological phenotype than that of USH2A variants carrying one truncating mutation and one missense mutation, suggesting a possible genotype-phenotype correlation. The understanding of audiological complexity associated with USH2A will be helpful for genetic counseling and treatment starategy.
