Identification of a novel PLS1 heterozygous variant causing autosomal dominant non-syndromic hearing loss

Congenital disabling hearing impairment is a prevalent sensory deficit, affecting >30,000 newborns annually in China. Non-syndromic hearing loss (NSHL) accounts for a notable proportion of these cases, ~60% of which are attributed to genetic defects by heterogeneity. Although >120 genes have been linked to NSHL, a definitive molecular diagnosis remains elusive for approximately one-half of the individuals undergoing genetic testing. In the present study, a Chinese family with NSHL was investigated using next-generation sequencing of the affected members, with validation by Sanger sequencing. A novel variant was identified, namely plastin-1 (PLS1) c.981+5G>A. Functional analysis by reverse transcription PCR revealed that this variant induces exon skipping, establishing its pathogenic mechanism. PLS1 encodes the actin-bundling protein plastin-1, which is highly abundant in the stereocilia of hair cells. Recent studies have implicated PLS1 in hearing loss; therefore, the present study provides direct functional validation of its pathogenicity, expanding the pathogenic variation spectrum of PLS1 and offering valuable insights into clinical diagnostic advancements and prenatal screening.