PSAP-Genomic-Regions: A Method Leveraging Population Data to Prioritize Coding and Non-Coding Variants in Whole Genome Sequencing for Rare Disease Diagnosis.

Autor: Ogloblinsky MC; Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France., Bocher O; Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France.; Institute of Translational Genomics, Helmholtz Zentrum München, Munich, Germany., Aloui C; Inserm, NeuroDiderot, Unité Mixte de Recherche, Université Paris Cité, Paris, France., Leutenegger AL; Inserm, NeuroDiderot, Unité Mixte de Recherche, Université Paris Cité, Paris, France., Ozisik O; INSERM, Marseille Medical Genetics (MMG), Aix Marseille University, Marseille, France., Baudot A; INSERM, Marseille Medical Genetics (MMG), Aix Marseille University, Marseille, France., Tournier-Lasserve E; Inserm, NeuroDiderot, Unité Mixte de Recherche, Université Paris Cité, Paris, France.; Assistance Publique-Hôpitaux de Paris, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France., Castillo-Madeen H; Division of Genetics, Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, USA., Lewinsohn D; Division of Genetics, Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, USA., Conrad DF; Division of Genetics, Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, USA., Génin E; Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France.; Centre Hospitalier Régional Universitaire de Brest, Brest, France., Marenne G; Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France.
Jazyk: angličtina
Zdroj: Genetic epidemiology [Genet Epidemiol] 2025 Jan; Vol. 49 (1), pp. e22593. Date of Electronic Publication: 2024 Sep 24.
DOI: 10.1002/gepi.22593
Abstrakt: The introduction of Next-Generation Sequencing technologies in the clinics has improved rare disease diagnosis. Nonetheless, for very heterogeneous or very rare diseases, more than half of cases still lack molecular diagnosis. Novel strategies are needed to prioritize variants within a single individual. The Population Sampling Probability (PSAP) method was developed to meet this aim but only for coding variants in exome data. Here, we propose an extension of the PSAP method to the non-coding genome called PSAP-genomic-regions. In this extension, instead of considering genes as testing units (PSAP-genes strategy), we use genomic regions defined over the whole genome that pinpoint potential functional constraints. We conceived an evaluation protocol for our method using artificially generated disease exomes and genomes, by inserting coding and non-coding pathogenic ClinVar variants in large data sets of exomes and genomes from the general population. PSAP-genomic-regions significantly improves the ranking of these variants compared to using a pathogenicity score alone. Using PSAP-genomic-regions, more than 50% of non-coding ClinVar variants were among the top 10 variants of the genome. On real sequencing data from six patients with Cerebral Small Vessel Disease and nine patients with male infertility, all causal variants were ranked in the top 100 variants with PSAP-genomic-regions. By revisiting the testing units used in the PSAP method to include non-coding variants, we have developed PSAP-genomic-regions, an efficient whole-genome prioritization tool which offers promising results for the diagnosis of unresolved rare diseases.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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