Introduction
Accurately interpreting the functional impact of gene variants at splice sites is a critical challenge in elucidating pathogenic mechanisms in complex genetic disorders. A recent study focusing on two Chinese families with hereditary hearing loss demonstrates how RDDC, as a cutting-edge bioinformatics analysis tool, provides crucial validation and analytical support during key variant assessment stages. This research not only identified novel compound heterozygous variants in the MARVELD2 gene but also leveraged the RDDC tool to provide strong evidence regarding the potential functional impact of a key splicing variant.
Research Background
Hereditary hearing loss is a common sensory deficit with complex genetic underpinnings. In this study, researchers performed targeted next-generation sequencing on two families with non-syndromic hearing loss, uncovering novel variants in the MARVELD2 gene. The tricellulin protein, encoded by MARVELD2, is crucial for maintaining the barrier function of the inner ear sensory epithelium.
Key Variant Analysis
Splice Site Variant Discovery
Among the three variants detected, c.1331+1G>A was particularly noteworthy. Located near a canonical splice site, it theoretically could severely affect mRNA maturation. To investigate its specific impact, the team first used the SpliceAI tool for initial prediction, which suggested the variant might alter the original splice site and activate a new one downstream.
RDDC Tool Validation
To further corroborate this prediction and conduct a more in-depth analysis, the researchers then employed the RDDC tool. RDDC's analysis results explicitly supported SpliceAI's prediction, reaffirming that the c.1331+1G>A variant is highly likely to cause a shift in the splice site and activate a cryptic site. This dual validation provided strong in silico evidence for the variant's potential pathogenicity. Although the variant was ultimately classified as a "Variant of Uncertain Significance" (VUS) according to ACMG/AMP guidelines due to the lack of subsequent functional experimental confirmation, the analytical results provided by RDDC were undoubtedly an indispensable component in assessing its clinical significance.
Research Significance
This study ultimately confirmed that the novel compound heterozygous MARVELD2 variants were the cause of autosomal recessive sensorineural hearing loss in these families, expanding the mutation spectrum for this gene. Throughout this process, the application of the RDDC tool clearly demonstrated its value in modern genetics research: it can cross-validate predictions from other tools, offering researchers reliable analytical direction and decision support when faced with complex variants of unknown function, thereby deepening the understanding of disease molecular mechanisms.
Content Source and Disclaimer
This article is a compilation and interpretation of the scientific study cited below, intended to highlight the application of RDDC bioinformatics tools. All research data and conclusions belong to the original authors and publication.
Original Article:
Wang L, Guan J, Yang J, et al. Novel compound heterozygous variants in MARVELD2 causing autosomal recessive hearing loss in two Chinese families. Journal of Translational Medicine. 2023 Mar 23;21(1):241.
Article Link:
https://pubmed.ncbi.nlm.nih.gov/39078259/
