Splice-altering variant in TECTA as a cause of hearing loss DFNA8/12

Abstract

Purpose The aim of this study was to determine the genetic cause of early onset autosomal dominant hearing loss segregating in five-generation kindred of Chinese descent and provide preimplantation genetic testing for them. Methods Clinical examination, pedigree analysis, exome sequencing, minigene-based splicing analysis and in vivo RNA analysis were carried out on the family. Preimplantation genetic testing (PGT) for the causative variation and chromosome aneuploidis based on SNP analysis has been used to avoid transmission of hearing loss in this family. Results All the affected individuals presented with moderate down-sloping hearing loss and whole-exome sequencing identified a novel splice-site variant c.5383 + 6T > A in the tested subjects within the TECTA locus. Genotyping of all the 32 family members confirmed segregation of this variant and the deafness phenotype in the extended family. Functional analysis of RNA indicated that c.5383 + 6T > A is a pathogenic splice-site variant and should be considered for diagnostic purposes. Furthermore, a successful singleton pregnancy with no variant in the site c.5383 + 6 within TECTA locus was established and a healthy male child was born by PGT. Conclusion We have identified a novel variant c.5383 + 6T > A in TECTA ZA-ZP inter-domain, which could be contributing to in early onset autosomal dominant hearing loss phenotype,The implications of our study are valuable in the clinical diagnosis, prognosis, and treatment of patients with TECTA pathogenic variants.