Case Overview
Accurate assessment of pathogenicity is crucial in diagnosing rare genetic disorders like Bone Marrow Failure Syndrome Type 1 (BMFS1), especially for diseases with non-specific clinical phenotypes. Evaluating novel variants, particularly those at splice sites, often presents a challenge.
A recent study on a pediatric BMFS1 patient demonstrates the key role of the RDDC RNA Splicer tool in assisting the pathogenicity assessment of a novel splicing variant. Utilizing RDDC's predictions in conjunction with ACMG guidelines, the study successfully classified a novel de novo splice site variant in the SRP72 gene as "likely pathogenic," providing essential support for the patient's timely diagnosis and subsequent hematopoietic stem cell transplantation (HSCT).
Research Challenge: Identifying the Cause of Rare Bone Marrow Failure
This study focused on a 6-year-old male child presenting with severe pancytopenia and extremely hypoplastic bone marrow. After excluding other common causes of bone marrow failure, the research team employed Next-Generation Sequencing (NGS) targeting genes associated with bone marrow failure syndromes.
This revealed a novel heterozygous variant in the SRP72 gene: c.1502+1G>A. Sanger sequencing confirmed this variant was de novo (absent in both parents) and unreported in public databases. Located at a canonical splice donor site, this variant was highly suspected to be pathogenic, but further bioinformatic analysis was needed to assess its precise impact on gene function.
RDDC's Prediction: Unveiling Potential Splicing Aberrations
To evaluate the potential consequences of the c.1502+1G>A variant on RNA splicing, the team utilized several bioinformatics tools, including RDDC RNA Splicer. RDDC's prediction provided specific mechanistic hypotheses, suggesting two primary aberrant splicing outcomes:
Predicted Splicing Outcomes
- Retention of a 229 bp intronic sequence: Part of the intron might be incorrectly retained in the mature mRNA.
- Skipping of exon 15: The entire exon 15 could be removed during mRNA maturation.
Both predictions clearly indicated that the variant would likely cause a frameshift and/or premature protein termination, resulting in a truncated, dysfunctional, or absent SRP72 protein. This prediction offered strong in silico evidence supporting the variant's pathogenicity.
Case Value: RDDC Assists VUS Pathogenicity Assessment, Guiding Clinical Decisions
Combining RDDC's prediction (indicating loss of function via splicing disruption, fitting PVS1 criteria) with the variant's de novo status (fitting PM6 criteria), the research team classified the c.1502+1G>A variant as "Likely Pathogenic" according to ACMG guidelines.
Clinical Impact
This definitive genetic diagnosis enabled the patient to receive timely, curative treatment with a matched sibling donor HSCT, leading to full recovery. This case highlights the value of RDDC RNA Splicer in interpreting splice site VUS. Even without in vitro functional validation, its accurate predictions can provide crucial support for clinical diagnosis and therapeutic decisions (such as proceeding with transplantation), preventing treatment delays that might occur while awaiting experimental results.
Key Insights
- RDDC RNA Splicer can accurately predict functional consequences of splice site variants
- Bioinformatics predictions can effectively support ACMG variant classification
- Timely genetic diagnosis is crucial for treatment decisions in rare diseases
- Multidisciplinary collaboration (genetics, hematology, transplant medicine) is key to successful treatment
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 X¹, Hao W², Geng A¹, Mu D¹. A Case of Bone Marrow Failure Syndrome Type 1 Caused by SRP72 Gene Mutation. China Medical Herald. 2024.
Affiliation: ¹Department of Pediatric Hematology, Inner Mongolia People's Hospital; ²(Information pending).
