Non-Syndromic Autosomal Dominant Hearing Loss: The First Italian Family Carrying a Mutation in the NCOA3 Gene

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.

Keywords: Italian family; NCOA3 gene; autosomal dominant inheritance; exome sequencing; non-syndromic hearing loss.

Figure 1

Pedigree of the Italian family. Pedigree of the four-generation family investigated in the present study. Filled symbols represent affected individuals. The age of each individual and the co-segregation of the NCOA3 variant with HL (NM_181659.3, c.2909G>C, p.(Gly970Ala)) are reported. Their ages are indicated followed by the terms y.o., meaning years old. The labels used to report the subjects’ genotypes are G/G for homozygous wild type and G/C for the individuals carrying the variant herein discussed in heterozygosis. Individuals with Roman numeric labels were analyzed in this study.

Figure 2

Audiograms of the Italian family. (A) Audiometric features, displayed as audiograms, were available for twelve members of the family. The thresholds of the right and left ears are shown for each patient. The audiometric patterns for patients IV:3 and IV:4 partially overlap. (B) Example of the progression of the hearing loss for patient III:10. In blue is displayed an audiogram performed in 2008, and in green, one of 2021 (Age-Related Typical Audiogram (ARTA)). Only the data for the best ear are reported.

Figure 3

DNA chromatograms, schematic representation of the protein domains and protein alignment. (A) Chromatograms displaying part of the NCOA3 sequence; on top, the wild-type sequence is shown, and on the bottom, that of an affected individual carrying the variant at the heterozygous state. The red box indicates the position of the variant. (B) Schematic representation of NCOA3 protein domains and the localization of the two mutations associated with ADNSHL. The helix loop helix domain is displayed as a green box; in orange, the PAS motif; in blue, low-complexity regions; in red, the coiled coil region; and in yellow, the SMART DUF1518 domain, commonly found in receptor co-activating proteins. Both the variants detected in the NCOA3 gene and associated with ADNSHL are located in the same undefined region of the protein; the one found in the Italian family is indicated with a purple star. (C) Protein alignment showing conservation of residue G970 across species.