PSAP-Genomic-Regions: A Method Leveraging Population Data to Prioritize Coding and Non-Coding Variants in Whole Genome Sequencing for Rare Disease Diagnosis.
non‐coding variants
rare diseases
variant prioritization
whole‐genome sequencing
Journal
Genetic epidemiology
ISSN: 1098-2272
Titre abrégé: Genet Epidemiol
Pays: United States
ID NLM: 8411723
Informations de publication
Date de publication:
24 Sep 2024
24 Sep 2024
Historique:
revised:
30
07
2024
received:
05
06
2024
accepted:
03
09
2024
medline:
25
9
2024
pubmed:
25
9
2024
entrez:
25
9
2024
Statut:
aheadofprint
Résumé
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.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : 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, and by the National Institutes of Health of the United States of America grants R01HD078641 and P50HD096723 to D. F. Conrad. This study was also supported by the INSERM GOLD Cross-Cutting program.
Informations de copyright
© 2024 Wiley Periodicals LLC.
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