Next-generation sequencing identified SPATC1L as a possible candidate gene for both early-onset and age-related hearing loss. (January 2019)

• Record Type: Journal Article
• Authors: Morgan, Anna; Vuckovic, Dragana; Krishnamoorthy, Navaneethakrishnan; Rubinato, Elisa; Ambrosetti, Umberto; Castorina, Pierangela; Franzè, Annamaria; Vozzi, Diego; La Bianca, Martina; Cappellani, Stefania; Di Stazio, Mariateresa; Gasparini, Paolo; Girotto, Giorgia
• Is Part Of: European journal of human genetics. Volume 27:Number 1(2019)
• Page Start: 70
• Page End: 79
• Publication Date: 2019-01
• Subjects: Human genetics -- Periodicals; Medical genetics -- Periodicals; 616.042
• DOI: 10.1038/s41431-018-0229-9
• Languages: English
• ISSNs: 1018-4813

Abstract

Abstract Hereditary hearing loss (HHL) and age-related hearing loss (ARHL) are two major sensory diseases affecting millions of people worldwide. Despite many efforts, additional HHL-genes and ARHL genetic risk factors still need to be identified. To fill this gap a large genomic screening based on next-generation sequencing technologies was performed. Whole exome sequencing in a 3-generation Italian HHL family and targeted re-sequencing in 464 ARHL patients were performed. We detected three variants inSPATC1L : a nonsense allele in an HHL family and a frameshift insertion and a missense variation in two unrelated ARHL patients. In silico molecular modelling of all variants suggested a significant impact on the structural stability of the protein itself, likely leading to deleterious effects and resulting in truncated isoforms. After demonstratingSpatc1l expression in mice inner ear, in vitro functional experiments were performed confirming the results of the molecular modelling studies. Finally, a candidate-gene population-based statistical study in cohorts from Caucasus and Central Asia revealed a statistically significant association ofSPATC1L with normal hearing function at low and medium hearing frequencies. Overall, the amount of different genetic data presented here (variants with early-onset and late-onset hearing loss in addition to genetic association with normal hearing function), together with relevant functional evidence, likely suggest a role ofSPATC1L in hearing function and loss.