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Ogloblinsky, M.C.* ; Bocher, O. ; Aloui, C.* ; Leutenegger, A.L.* ; Ozisik, O.* ; Baudot, A.* ; Tournier-Lasserve, E.* ; Castillo-Madeen, H.* ; Lewinsohn, D.* ; Conrad, D.F.* ; Genin, E.* ; Marenne, G.*

PSAP-Genomic-Regions: A method leveraging population data to prioritize coding and non-coding variants in whole genome sequencing for rare Disease diagnosis.

Genet. Epidemiol., DOI: 10.1002/gepi.22593 (2024)
DOI PMC
Open Access Green: Postprint online available 10/2025
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Non‐coding Variants ; Rare Diseases ; Variant Prioritization ; Whole‐genome Sequencing; Online Mendelian Inheritance; Framework; Pathogenicity; Genes
ISSN (print) / ISBN 0741-0395
e-ISSN 1098-2272
Journal Genetic Epidemiology
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Translational Genomics (ITG)
Grants This study was jointly supported by the French Priority Research Program on Rare Diseases "Programme Prioritaire de Recherche Maladies Rares du Programme français d'Investissements d'Avenir" and by the Britanny region through the ARED program to E. Génin,