PSAP-Genomic-Regions: A Method Leveraging Population Data to Prioritize Coding and Non-Coding Variants in Whole
Marie-Sophie C Ogloblinsky1, Ozvan Bocher1,2, Chaker Aloui3
1Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France.
Genetic Epidemiology
|September 25, 2024
Summary
A new method, PSAP-genomic-regions, enhances rare disease diagnosis by prioritizing genetic variants across the whole genome. This tool significantly improves variant ranking, aiding in identifying causes of undiagnosed genetic disorders.
Area of Science:
- Genomics
- Medical Genetics
Background:
- Next-Generation Sequencing (NGS) has advanced rare disease diagnosis, yet over half of cases remain undiagnosed, particularly for heterogeneous or rare conditions.
- Current variant prioritization methods are limited, especially for non-coding variants, hindering molecular diagnosis in complex genetic diseases.
Purpose of the Study:
- To extend the Population Sampling Probability (PSAP) method to the non-coding genome, creating PSAP-genomic-regions for whole-genome variant prioritization.
- To improve the diagnostic yield for rare and undiagnosed diseases by effectively ranking both coding and non-coding variants.
Main Methods:
- Developed PSAP-genomic-regions, utilizing functionally constrained genomic regions as testing units instead of genes.
- Evaluated the method using simulated exome and genome datasets with known pathogenic variants from ClinVar.
- Applied PSAP-genomic-regions to real sequencing data from patients with Cerebral Small Vessel Disease and male infertility.
Main Results:
- PSAP-genomic-regions significantly outperformed pathogenicity scores alone in ranking variants.
- Over 50% of non-coding ClinVar variants were ranked within the top 10 using PSAP-genomic-regions.
- Causal variants in all tested patients (Cerebral Small Vessel Disease and male infertility) were identified within the top 100 variants.
Conclusions:
- PSAP-genomic-regions is an effective whole-genome variant prioritization tool that incorporates non-coding regions.
- The method shows promise for diagnosing unresolved rare diseases by improving the identification of pathogenic variants.
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