Abstract
Autosomal dominant non-syndromic hearing loss (ADNSHL) has a broad phenotypic spectrum which includes bilateral, symmetrical, and high-frequency sensorineural hearing loss, that eventually progresses into hearing loss at all frequencies. Several genetic variations have been identified as causal factors underlying deafness, autosomal dominant 5 (DFNA5) gene-related hearing loss. Here, we report a novel mutation (c.991-1G > C) in DFNA5, which co-segregated with late-onset ADNSHL in a Chinese family and was identified via exome sequencing and Sanger sequencing of DNA from peripheral blood of the family members. Further sequencing of cDNA derived from peripheral blood mRNA revealed that the c.991-1G >C mutation led to the skipping of exon 8, which is a known pathogenic mechanism for DFNA5-related hearing loss.
Highlights
Genetic hearing loss is a common congenital sensory disorder worldwide
We recruited three members of a Chinese family affected by lateonset Autosomal dominant non-syndromic hearing loss (ADNSHL), including the proband (II-1) and his parents (Figure 1A)
All DFNA5 mutations reported to date are splice-site variants leading to the skipping of exon 8 (Table 1; Van Laer et al, 1998; Yu et al, 2003; Bischoff et al, 2004; Cheng et al, 2007; Park et al, 2010; Chai et al, 2014; Nishio et al, 2014; Li-Yang et al, 2015; Nadol et al, 2015; Booth et al, 2018; Wang et al, 2018; Booth et al, 2020)
Summary
Genetic hearing loss is a common congenital sensory disorder worldwide. In approximately 50% of cases, hearing loss is caused by genetic factors, and 70% of people with hereditary hearing loss are classified as cases of non-syndromic hearing loss, which is not associated with other diseases (Cunningham and Tucci, 2017). Numerous DFNA5-associated splice-site variations have been reported as pathogenic mutations for hearing loss. All these variations have a common effect of skipping exon 8 at the mRNA level, which results in an identical gain-of-function effect at the protein level. We report a novel pathogenic DFNA5 splice-site variant, which was identified in a Chinese family via exome sequencing and validated using Sanger sequencing. We recruited three members of a Chinese family affected by lateonset ADNSHL, including the proband (II-1) and his parents (Figure 1A). The pathogenicity of the variants was annotated using the Human Gene Mutation Database, ClinVar database, and standard variants of the American College of Medical Genetics and Genomics (ACMG) Location Mutation effect c.990+503_990+1691delins132 c.991–6C > G c.991–3C > A c.991–2A > G c.991–15_991–13del c.1183G > A c.1183+4A > G c.1183+1delG c.1154C > T c.1102C > G c.991–1G > C
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