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

이상연; 주광식; 오자영; 한진희; 박혜림; 이승민; 오두이; 우세준; 최병윤

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자료유형: 학술저널

저자정보: 이상연 주광식 오자영 한진희 박혜림 이승민 오두이 우세준 최병윤

저널정보: 대한이비인후과학회 Clinical and Experimental Otorhinolaryngology Clinical and Experimental Otorhinolaryngology 제13권 제2호

발행연도: 2020.1

수록면: 113 - 122 (10page)

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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.

참고문헌 (40)

참고문헌 신청

van Wijk E / 2004 / Identification of 51 novel exons of the Usher syndrome type 2A(USH2A)gene that encode multiple conserved functional domains and that are mutated in patients with Usher syndrome type II / Am J Hum Genet 74(4):738~744

Smith RJ / 1994 / Clinical diagnosis of the Usher syndrome : Usher Syndrome Consortium / Am J Med Genet 50(1):32~38

Ahmed ZM / 2003 / The molecular genetics of Usher syndrome / Clin Genet 63(6):431~444

Otterstedde CR / 2001 / A new clinical classification for Usher’s syndrome based on a new subtype of Usher’s syndrome type I / Laryngoscope 111(1):84~86

Spandau UH / 2002 / Prevalence and geographical distribution of Usher syndrome in Germany / Graefes Arch Clin Exp Ophthalmol 240(6):495~498

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