Reference : Identification of pathogenic variant enriched regions across genes and gene families
Scientific journals : Article
Life sciences : Genetics & genetic processes
Systems Biomedicine
Identification of pathogenic variant enriched regions across genes and gene families
Perez-Palma, Eduardo []
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Iqbal, Sumaiya []
Niestroj, Lisa-Marie []
Du, Juanjiangmeng []
Heyne, Henrike O. []
Castrillon, Jessica A. []
O'Donnell-Luna, Anne []
Nürnberg, Peter []
Palotie, Aarno []
Daly, Mark []
Lal, Dennis []
Genome Research
Cold Spring Harbor Laboratory Press
Yes (verified by ORBilu)
Cold Spring Harbor
[en] Missense variant interpretation is challenging. Essential regions for protein function are conserved among gene family members, and genetic variants within these regions are potentially more likely to confer risk to disease. Here, we generated 2,871 gene family protein sequence alignments involving 9,990 genes and performed missense variant burden analyses to identify novel essential protein regions. We mapped 2,219,811 variants from the general population into these alignments and compared their distribution with 76,153 missense variants from patients. With this gene family approach, we identified 465 regions enriched for patient variants spanning 41,463 amino acids in 1,252 genes. As a comparison, testing the same genes individually we identified less patient variant enriched regions involving only 2,639 amino acids and 215 genes. Next, we selected de novo variants from 6,753 patients with neurodevelopmental disorders and 1,911 unaffected siblings, and observed an 8.33-fold enrichment of patient variants in our identified regions (95% C.I.=3.90-Inf, p-value = 2.72x10-11). Using the complete ClinVar variant set, we found that missense variants inside the identified regions are 106-fold more likely to be classified as pathogenic in comparison to benign classification (OR = 106.15, 95% C.I = 70.66-Inf, p-value < 2.2 x 10-16). All pathogenic variant enriched regions (PERs) identified are available online through the “PER viewer” a user-friendly online platform for interactive data mining, visualization and download. In summary, our gene family burden analysis approach identified novel pathogenic variant enriched regions in protein sequences. This annotation can empower variant interpretation.
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)

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