Clin Exp Otorhinolaryngol.  2020 May;13(2):113-122. 10.21053/ceo.2019.00990.

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

• Lee SY
• Joo K
• Oh J
• Han JH
• Park HR
• Lee S
• Oh DY
• Woo SJ
• Choi BY

• KMID: 2500283
• DOI: http://doi.org/10.21053/ceo.2019.00990

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.

Keyword

Usher Syndrome; USH2A; Mutation

Figure

• 

  Fig. 1. Audiological phenotypes of affected subjects with Usher syndrome type II (USH2) variants. (A) SB237-461, bilateral severe down-sloping sensorineural hearing loss (SNHL). (B) SB354-692, profound down-sloping SNHL on the right ear and severe down-sloping SNHL on the left ear. Red and blue lines represent the right and left ear hearing thresholds, respectively. Numbers with a percentage demonstrate the speech audiometry score in each evaluated ear. SDS, speech discrimination score.

• 

  Fig. 2. Representative color fundus photographs and optical coherence tomography (OCT) images for two patients with typical features of retinitis pigmentosa. (A) A right fundus image from patient SB237-461 exhibits diffuse retinal pigmentary changes, vascular attenuation and waxy disc pallor. (B) An ipsilateral spectral-domain OCT image shows the diffuse disruption of photoreceptors (red arrowheads) in the macula. (C) A left fundus image from patient SB354-692 shows diffuse retinal degeneration but relatively preserved macula. (D) An OCT image shows the preservation of photoreceptors in fovea (blue arrows) whereas extrafoveal photoreceptors disappeared (red arrowheads).

• 

  Fig. 3. Sanger sequencing results of SB237 and SB354, as well as the conservation of residue p.R2723X and p.C608Y from a various species. (A) SB237: candidate variants of USH2A with recessive inheritance (c.8167C>T: p.R2723X and c.1823G>A: p.C608Y) on the basis of Sanger sequencing chromatograms. (B) The residues p.R2723X and p.C608Y were well conserved in known USH2A orthologs across different species. (C) SB354: candidate variants of USH2A with recessive inheritance (c.14835delT: p.S4945fs and c.13112_13115delAAAT: p.G4371fs) according to Sanger sequencing chromatograms. Het, heterozygous.

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