Whole Exome Sequencing Identifies Novel Splicing Variants in the PTPRQ Gene and Their Mechanisms in Autosomal Recessive Non-Syndromic Hearing Loss.

Objectives: The PTPRQ gene is essential for preserving the structure and function of stereocilia in inner ear. However, research on splicing mutations within this gene is limited. This study aims to investigate novel splicing mutations in PTPRQ, clarify their molecular mechanisms, and provide new insights into the genetic factors associated with hearing loss, ultimately enhancing diagnostic accuracy.

Method: Clinical data and peripheral blood samples were obtained from members of a family with congenital hearing loss. Variants were identified through high-throughput sequencing and confirmed by Sanger sequencing to ensure genealogical co-segregation. The splicing effects of PTPRQ variants were evaluated using bioinformatics tools and minigene assays.

Results: We used whole exome sequencing to identify novel double compound heterozygous splice-altering variants (c.5426+1 G>A and c.6603-3 T>G) in the PTPRQ gene with DFNB84A. We molecularly characterized these variants, and they were found to co-segregate with the disease within the family. Minigene assays and Sanger sequencing confirmed that the c.6603-3 T > G variant caused exon 43 skipping, resulting in a frameshift mutation (p.Ser2201ArgfsTer112). Further bioinformatic analysis supported these findings.

Conclusions: This study identifies a novel compound heterozygous splicing variant in the PTPRQ gene in a Chinese family with DFNB84A, expanding the known spectrum of PTPRQ mutations. These findings enhance the understanding of PTPRQ-related hearing loss and may aid in early diagnosis, prevention, and therapeutic strategies.