Identification of pathogenic variant enriched regions across genes and gene families

Abstract

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 2871 gene-family protein sequence alignments involving 9990 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 1252 genes. As a comparison, by testing the same genes individually, we identified fewer patient variant enriched regions, involving only 2639 amino acids and 215 genes. Next, we selected de novo variants from 6753 patients with neurodevelopmental disorders and 1911 unaffected siblings and observed an 8.33-fold enrichment of patient variants in our identified regions (95% C.I. = 3.90-Inf, P-value = 2.72 × 10 −11). By 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 × 10 −16). All pathogenic variant enriched regions (PERs) identified are available online through "PER viewer," a user-friendly online platform for interactive data mining, visualization, and download. In summary, our gene-family burden analysis approach identified novel PERs in protein sequences. This annotation can empower variant interpretation.

Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

“…Usage of the paralog conservation metric in drug target design could therefore have the potential in ruling out or to reduce such cross-reactivity effects. Paralog conservation plots are available on the PER [37] webpage (http://per.broadinstitute.org).…”

Variants in the degron ofAFF3cause a multi-system disorder with mesomelic dysplasia, horseshoe kidney and developmental and epileptic encephalopathy

“…This highly conserved 9 amino acid sequence [xPxAxVxPx] ( Figure 1A-B ) mediates interaction with the SIAH E3 ubiquitin ligase and regulates their degradation 1 . According to pathogenic variant enriched regions (PER) 43 , the degron is predicted to be constrained within the ALF family. Pathogenicity of the four de novo AFF3 identified variants is further supported by the three-dimensional representation of part of the encoded peptide ( Figure 1D ).…”

Genomic Landscape and Mutational Spectrum of ADAMTS Family Genes in Mendelian Disorders Based on Gene Evidence Review for Variant Interpretation

“…To evaluate the possibility of yet-to-be-discovered Mendelian disorders caused by other ADAMTS genes, we applied two recently validated prediction algorithms [20,21] for missense burden estimation by regions across genes. Although only one algorithm predicted that four genes (ADAMTS6, ADAMTS9, ADAMTS10, ADAMTS14) possessed missense intolerance regions, pathogenic missense mutations in ADAMTS9 and ADAMTS10 indeed account for relatively high proportions among mutation types.…”

“…To enhance the analysis accuracy, we profiled all aspects of variants, including population allele frequency, prediction algorithm results, and conservation status across species. For gene evaluation in terms of cause-and-effect relationships for hereditary disorders, we applied two recently published prediction algorithms for missense variant burden (i.e., PER (pathogenic mutation enriched regions) viewer [20] and MTR (missense tolerance regions) viewer [21]) in ADAMTS genes. These tools provided a statistical framework to identify gene regions with missense variation intolerance or pathogenic mutation enriched regions.…”

“…Percentages of frameshift/nonsense/splicing variants were dominant in most causative ADAMTS genes, although missense variants were more predominant in ADAMTS18. To predict the possibility of a missense mutational burden at "hot spots" on ADAMTS genes, two recently validated prediction tools (i.e., PER-viewer [20] and MTR-viewer [21]) were utilized. As PER-viewer considers the positional conservation status among paralogs, each ADAMTS gene was compared to other genes within the ADAMTS family.…”