RT Journal Article SR Electronic T1 Congenital valvular defects associated with deleterious mutations in the PLD1 gene JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 278 OP 286 DO 10.1136/jmedgenet-2016-104259 VO 54 IS 4 A1 Asaf Ta-Shma A1 Kai Zhang A1 Ekaterina Salimova A1 Alma Zernecke A1 Daniel Sieiro-Mosti A1 David Stegner A1 Milena Furtado A1 Avraham Shaag A1 Zeev Perles A1 Bernhard Nieswandt A1 Azaria J J T Rein A1 Nadia Rosenthal A1 Aaron M Neiman A1 Orly Elpeleg YR 2017 UL http://jmg.bmj.com/content/54/4/278.abstract AB Background The underlying molecular aetiology of congenital heart defects is largely unknown. The aim of this study was to explore the genetic basis of non-syndromic severe congenital valve malformations in two unrelated families.Methods Whole-exome analysis was used to identify the mutations in five patients who suffered from severe valvular malformations involving the pulmonic, tricuspid and mitral valves. The significance of the findings was assessed by studying sporulation of yeast carrying a homologous Phospholipase D (PLD1) mutation, in situ hybridisation in chick embryo and echocardiography and histological examination of hearts of PLD1 knockout mice.Results Three mutations, p.His442Pro, p.Thr495fs32* and c.2882+2T>C, were identified in the PLD1 gene. The mutations affected highly conserved sites in the PLD1 protein and the p.His442Pro mutation produced a strong loss of function phenotype in yeast homologous mutant strain. Here we show that in chick embryos PLD1 expression is confined to the forming heart (E2–E8) and homogeneously expressed all over the heart during days E2–E3. Thereafter its expression decreases, remaining only adjacent to the atrioventricular valves and the right ventricular outflow tract. This pattern of expression follows the known dynamic patterning of apoptosis in the developing heart, consistent with the known role of PLD1 in the promotion of apoptosis. In hearts of PLD1 knockout mice, we detected marked tricuspid regurgitation, right atrial enlargement, and increased flow velocity, narrowing and thickened leaflets of the pulmonic valve.Conclusions The findings support a role for PLD1 in normal heart valvulogenesis.