Introduction
Deep intronic variants (DIVs) are a significant challenge in Whole Exome Sequencing (WES) data analysis, as their functional consequences are difficult to predict. A recent rare case report on Congenital Eyelid Coloboma (CEC) clearly demonstrates the critical value of the RDDC-RNA splicer tool in overcoming this hurdle. Through a precise in silico prediction, the study provided the first crucial evidence linking a novel de novo intronic variant in the JMJD6 gene to the CEC phenotype.
The Clinical Challenge: A VUS in Discordant Identical Twins
The challenge in this study arose from a unique case: one identical twin sister presented with a full-thickness defect of her left upper eyelid, while the other twin was phenotypically normal. This discordance significantly complicated the genetic analysis. WES detected a novel de novo heterozygous variant in the patient: c.941+75G>T in the JMJD6 gene.
This variant was located deep within an intron, absent from gnomAD and other databases, making its pathogenicity completely unknown. The core questions were: Is this "Variant of Uncertain Significance" (VUS) the cause? And if so, how does it function?
RDDC's Precise Prediction: Unmasking a Pseudoexon Insertion
To answer this, the research team used the RDDC-RNA splicer tool to predict the variant's impact on splicing. RDDC's analysis provided the key, specific pathogenic mechanism: the c.941+75G>T variant was predicted to cause the abnormal insertion of a 485 bp pseudoexon into the mature mRNA.
This prediction was highly significant. It clearly indicated that the intronic variant was not benign, but would instead lead to a frameshift and premature protein termination, thereby severely disrupting JMJD6 protein function.
Case Implications
This case powerfully demonstrates that RDDC-RNA splicer is a robust tool for researchers navigating the vast number of intronic VUS in WES/WGS data. It moves beyond a simple risk score to provide specific, testable molecular mechanisms (like pseudoexon insertion), offering a clear target and theoretical basis for subsequent functional experiments (such as RNA-seq).
This RDDC prediction was the critical first step in linking the JMJD6 gene to CEC.
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:
Case report: A novel intronic JMJD6 likely pathogenic variant (c.941+75G > T) associated with congenital eyelid coloboma in one of the identical twin sisters.
Article Link: https://pubmed.ncbi.nlm.nih.gov/40034743/
