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Fig. 2 | Genome Medicine

Fig. 2

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

Fig. 2

Assessment of paralog conservation. a Identification of missense variant gene family enrichment in NDD patients for paralog-conserved missense variants. NDD-associated missense variants are enriched in paralog-conserved sites. y-axis: missense variant enrichment analysis considering only paralog non-conserved sites across genes of each gene family (para_zcore ≤ 0, pmissense_not_conserved). x-axis: missense variant enrichment analysis considering only paralog-conserved sites (para_zcore > 0, pmissense_conserved). None of the gene families shows exome-wide significant enrichment for paralog non-conserved sites. Twenty-six gene families (depicted by circles) show exome-wide significant de novo missense variant burden at paralog-conserved sites. The significance threshold was calculated by Bonferroni correction for testing 5 × 2871 gene families (P = 3.48 × 10−6) and is depicted by the blue dotted line. b Enrichment of missense variants in paralog-conserved sites in genes with significant DNM burden in this study. Distribution of NDD patient missense, nonsense, and synonymous para_zscores for all non-significantly enriched genes (top) and genes significantly enriched for DNM missense variants (bottom panel) depicted by density plots. DNM burden was calculated using the mutational framework described by Samotcha et al. (for details, see the “Methods” section). Genes were categorized into two groups: those with a significant burden and those without. In disease-associated genes (those with DNM burden), missense variants were enriched at paralog-conserved sites relative to missense variants in non-significantly enriched genes (P value < 2.2E−16, top vs. bottom panel). Missense variants in genes without DNM burden were not enriched at paralog-conserved sites compared to synonymous variants (P value = 0.1157, top panel). In genes with DNM burden (bottom panel), missense variants were significantly enriched at paralog-conserved sites compared to synonymous variants (P value = 3.01 × 10−4). The same test for nonsense variants vs. synonymous variants did not show significant differences in paralog conservation (P value = 0.3913). P values were calculated using a Wilcoxon test

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