Eprint already available on another site (E-prints, Working papers and Research blog)
Identification of pathogenic variant enriched regions across genes and gene families
Pérez-Palma, Eduardo; May, Patrick; Iqbal, Sumaiya et al.
2019
 

Files


Full Text
641043.full.pdf
Publisher postprint (806.07 kB)
Download

All documents in ORBilu are protected by a user license.

Send to



Details



Keywords :
Gene families; paralogs; Missense variants; Variant classification
Abstract :
[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 65,034 missense variants from patients. With this gene family approach, we identified 398 regions enriched for patient variants spanning 33,887 amino acids in 1,058 genes. As a comparison, testing the same genes individually we identified less patient variant enriched regions involving only 2,167 amino acids and 180 genes. Next, we selected de novo variants from 6,753 patients with neurodevelopmental disorders and 1,911 unaffected siblings, and observed a 5.56-fold enrichment of patient variants in our identified regions (95% C.I. =2.76-Inf, p-value = 6.66×10−8). Using an independent ClinVar variant set, we found missense variants inside the identified regions are 111-fold more likely to be classified as pathogenic in comparison to benign classification (OR = 111.48, 95% C.I = 68.09-195.58, p-value < 2.2e−16). All patient variant enriched regions identified (PERs) are available online through a user-friendly platform for interactive data mining, visualization and download at http://per.broadinstitute.org. In summary, our gene family burden analysis approach identified novel patient variant enriched regions in protein sequences. This annotation can empower variant interpretation.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Pérez-Palma, Eduardo
May, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Iqbal, Sumaiya
Niestroj, Lisa-Marie
Du, Juanjiangmeng
Heyne, Henrike
Castrillon, Jessica
O’Donnell-Luria, Anne
Nürnberg, Peter
Palotie, Aarno
Daly, Mark
Lal, Dennis
Language :
English
Title :
Identification of pathogenic variant enriched regions across genes and gene families
Publication date :
17 May 2019
Focus Area :
Systems Biomedicine
Available on ORBilu :
since 07 July 2019

Statistics


Number of views
83 (0 by Unilu)
Number of downloads
79 (3 by Unilu)

OpenCitations
 
2

Bibliography


Similar publications



Contact ORBilu