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A Novel Biallelic Variant in Cdh23 Gene in a Family With Atypical Ush1d Manifestation: A Literature Review and Investigation of Genotype-Phenotype Correlation Publisher Pubmed



Khorram E1 ; Iravani O2 ; Khorrami M1 ; Amini M3 ; Jahanian S4 ; Nilforoush MH5 ; Mousavi SR6, 7 ; Ehsanifard M8 ; Kheirollahi M1
Authors
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Authors Affiliations
  1. 1. Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran
  3. 3. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Ophthalmology Division, Ganjavian Hospital, Dezful, Iran
  5. 5. Audiology Department, School of Rehabilitation Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
  6. 6. Cellular, Molecular and Genetics Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
  7. 7. Medical Genetics Research Center of Genome, Isfahan University of Medical Sciences, Isfahan, Iran
  8. 8. Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran

Source: Audiology and Neurotology Published:2023


Abstract

Introduction: Usher syndrome (USH) is an autosomal recessive disorder that predominantly affects hearing, vision, and, in some cases, vestibular function. USH, according to the onset age, severity, and progression of symptoms, is categorized into four main types. In addition, there are a significant number of reports that patients' manifestations deviate from canonical phenotypic criteria of main types of USH, which are named atypical USH. CDH23 is the second most common USH gene in which its defects result in USH1D, non-syndromic autosomal recessive deafness-12 (DFNB12), and in a few cases, atypical USH1D. While some studies have suggested that missense and truncating damaging variants in the CDH23 gene cause DFNB12 and USH1D, respectively, no genotype-phenotype correlation for atypical USH1D has been established. Methods: Using whole-exome sequencing, we studied an Iranian family with two affected siblings who manifested congenital bilateral hearing loss, late-onset nyctalopia, retinitis pigmentosa, and normal vestibular function, indicating that their clinical symptoms are consistent with USH2. Results: Whole-exome data analysis revealed a novel bi-allelic nonsense variant (c.6562G>T; p.Glu2188Ter) in the CDH23 gene, which was confirmed by Sanger sequencing. Surprisingly, CDH23 is a member of the USH1 genes; therefore, our patients suffered from atypical USH1D. Also, by conducting a literature review, we provided a clinical and mutational profile of all reported patients with atypical manifestations or those who refuted the claimed genotype-phenotype correlation. Conclusion: By reporting a novel damaging variant, we expand the mutational spectrum of the CDH23 gene that leads to atypical USH1D. Also, reviewing the literature shows that, contrary to previous claims, different genotypes occur in the CDH23 gene allelic disorders, and there is no clear-cut genotype-phenotype correlation. © 2023 S. Karger AG. All rights reserved.
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