RT Journal Article
SR Electronic
T1 Identification of pathogenic variant enriched regions across genes and gene families
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 641043
DO 10.1101/641043
A1 Eduardo Pérez-Palma
A1 Patrick May
A1 Sumaiya Iqbal
A1 Lisa-Marie Niestroj
A1 Juanjiangmeng Du
A1 Henrike Heyne
A1 Jessica Castrillon
A1 Anne O’Donnell-Luria
A1 Peter Nürnberg
A1 Aarno Palotie
A1 Mark Daly
A1 Dennis Lal
YR 2019
UL http://biorxiv.org/content/early/2019/05/17/641043.abstract
AB 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.