Introduction
Accurately assessing the potential pathogenicity of each variant, especially non-coding ones, is crucial for understanding clinical heterogeneity and developing precision medicine strategies in complex neurodegenerative diseases like Early-Onset Parkinson's Disease (EOPD), where multiple gene variants often coexist. A study on Chinese EOPD families highlights the value of the RDDC AI Tool RNA Splicing Prediction Model in analyzing such complex genetic backgrounds. The study utilized the RDDC tool to predict potential aberrant splicing caused by an intronic variant in the LRRK2 gene, providing important clues for evaluating its possible modifying effect in the context of a homozygous PRKN gene deletion.
Clinical Challenge: Multiple Gene Variants in an EOPD Family
The study analyzed two EOPD families. Notably, the patient in Family 2 carried not only a clearly pathogenic homozygous deletion of exons 3-4 in the PRKN gene but also two additional variants in other Parkinson's-related genes: a nonsense mutation in the PINK1 gene (c.1474C>T) and a novel intronic splicing variant in the LRRK2 gene (c.4827+6T>A).
Compared to the patient in Family 1, who had only compound heterozygous PRKN variants, the patient in Family 2 exhibited earlier onset, more severe symptoms, faster progression, and significant autonomic dysfunction. This suggested that the LRRK2 or PINK1 variants might be modifying the phenotype associated with the PRKN deletion. However, the functional consequence of the intronic c.4827+6T>A variant was unknown and required assessment.
RDDC's Precise Prediction: Revealing Potential Impact of the LRRK2 Splicing Variant
To evaluate the potential impact of the LRRK2 c.4827+6T>A intronic variant on RNA splicing, the research team employed the RDDC AI Tool RNA Splicing Prediction Model. This advanced algorithm predicts changes in splicing patterns that a variant might induce. For this specific variant, RDDC predicted it could lead to the erroneous insertion of a 332 bp intronic sequence into the mature mRNA.
This prediction directly pointed to a potential pathogenic mechanism: such a long insertion would almost certainly cause a frameshift and introduce a premature termination codon, ultimately resulting in a truncated and likely non-functional LRRK2 protein. Although the homozygous PRKN deletion was the primary cause of EOPD in this family, the potential LRRK2 protein dysfunction predicted by RDDC could explain the more severe clinical phenotype observed in the Family 2 patient.
Case Value: RDDC Aids Pathogenicity Assessment in Complex Genetic Backgrounds
This case demonstrates the utility of the RDDC RNA Splicing Prediction Model in handling complex genetic scenarios involving multiple variants. Even when a primary high-impact pathogenic variant is identified (like the homozygous PRKN deletion), the RDDC tool can still help researchers evaluate the potential functional impact and contribution of co-occurring variants, especially non-coding splicing variants.
The specific molecular mechanism predicted by RDDC (e.g., the 332 bp insertion) provides valuable clues for understanding the clinical heterogeneity of EOPD and underscores the importance of multi-gene panel testing in EOPD patients for a comprehensive assessment of genetic risk and tailored clinical management.
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:
Liao S¹,², Chen H¹, Liu M², Pan C², Luo A², Zhang L². Clinical characteristics and genetic testing of families with early-onset Parkinson's disease caused by PRKN gene mutations. Chinese Journal of Neurology. 2023;56(1):47-53.
Affiliation: ¹Department of Neurology, Liuzhou People's Hospital Affiliated to Guangxi Medical University; ².
