Abstract
Hearing loss (HL) is the most frequent sensory disorder, affecting about 1–3 per 1000 live births, with more than half of the cases attributable to genetic causes. Despite the fact that many HL causative genes have already been identified, current genetic tests fail to provide a diagnosis for about 40% of the patients, suggesting that other causes still need to be discovered. Here, we describe a four-generation Italian family affected by autosomal dominant non-syndromic hearing loss (ADNSHL), in which exome sequencing revealed a likely pathogenic variant in NCOA3 (NM_181659.3, c.2909G>C, p.(Gly970Ala)), a gene recently described as a novel candidate for ADNSHL in a Brazilian family. A comparison between the two families highlighted a series of similarities: both the identified variants are missense, localized in exon 15 of the NCOA3 gene and lead to a similar clinical phenotype, with non-syndromic, sensorineural, bilateral, moderate to profound hearing loss, with a variable age of onset. Our findings (i.e., the identification of the second family reported globally with HL caused by a variant in NCOA3) further support the involvement of NCOA3 in the etiopathogenesis of ADNSHL, which should, thus, be considered as a new gene for autosomal dominant non-syndromic hearing loss.
Highlights
Hearing loss (HL) is the most frequent sensory disorder, affecting about 1–3 per 1000 live births [1]
Up to 80% of congenital cases are attributable to genetic defects, which can lead to syndromic hearing loss with other organ abnormalities, or non-syndromic HL, which represents the majority of the cases (i.e., 70%, recent findings suggest that this percentage might be lower) [2]
Several studies demonstrated a lower detection rate for autosomal dominant Non-syndromic hearing loss (NSHL) families (ADNSHL) [4,5], which might be due to the phenotype variability among patients that leads to difficulties in defining a correct genotype–phenotype correlation and, a proper molecular diagnosis [6]
Summary
Hearing loss (HL) is the most frequent sensory disorder, affecting about 1–3 per 1000 live births [1]. Up to 80% of congenital cases are attributable to genetic defects, which can lead to syndromic hearing loss with other organ abnormalities, or non-syndromic HL, which represents the majority of the cases (i.e., 70%, recent findings suggest that this percentage might be lower) [2]. Non-syndromic hearing loss (NSHL) can be inherited as an autosomal recessive disease (i.e., 80%), autosomal dominant (i.e., 15–20%) or X-linked, mitochondrial or Ylinked, which, account for less than 1% of the total cases [1]. Definition of the molecular cause of NSHL is hampered by the high clinical and genetic heterogeneity of the disease, with more than 123 genes and 170 loci described far (Hereditary Hearing Loss Homepage, https://hereditaryhearingloss.org/, accessed on 25 May 2021). Several studies demonstrated a lower detection rate for autosomal dominant NSHL families (ADNSHL) [4,5], which might be due to the phenotype variability among patients that leads to difficulties in defining a correct genotype–phenotype correlation and, a proper molecular diagnosis [6]
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