Fig. 3: Truncating variants in PMEPA1 result in Loeys–Dietz syndrome.
From: Genetic association analysis of 77,539 genomes reveals rare disease etiologies
a, Pedigrees for the three probands in the 100KGP (discovery cohort) heterozygous for the frameshift insertion predicting p.S209Qfs*3 and probands from replication cohorts, including one from the 100KGP Pilot Programme heterozygous for the frameshift deletion predicting p.S209Afs*61, three of Japanese ancestry heterozygous for p.S209Qfs*3 and one Belgian pedigree heterozygous for a frameshift deletion encoding p.P207Qfs*3. All variant consequences are shown with respect to the canonical transcript of PMEPA1, ENST00000341744.8. b, HPO terms present in at least three of the four PMEPA1 FTAAD families, excluding redundant terms within each level of frequency, alongside their frequency in four PMEPA1 FTAAD families and the other 589 unexplained FTAAD families. Terms are ordered by P values obtained by a Fisher exact test of association between the term’s presence in an FTAAD family and whether the family is one of the four PMEPA1 families. Terms were declared significant (indicated by an asterisk) or not significant (NS) by comparing their Fisher test P values and rank with a null distribution of equivalent pairs obtained by permutation (10,000 replicates). For each rank, the P value of the term on the fifth percentile was used as an upper bound for declaring an association significant, provided all terms at higher ranks were also significant. The P values for each term were as follows: ‘Dolichocephaly’, P = 2.9 × 10−4; ‘Abnormal axial skeleton morphology’, P = 6.7 × 10−3; ‘Striae distensae’, P = 0.013; ‘Pes planus’, P = 0.014; ‘Ascending tubular aorta aneurysm’, P = 0.62. c, Graph showing PMEPA1 and genes with high evidence (green) of association with FTAAD in PanelApp. Edges connect genes where the string-db v.11.527 confidence score for physical interactions between corresponding proteins was >0.6. Genes known to be associated with Loeys–Dietz syndrome are highlighted in blue. PMEPA1 is highlighted yellow. d, Schematic showing the effects of each variant at the cDNA and amino acid level and on the protein product.
