Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.

The impact of genotype on endocrine complications in thalassaemia major.

BACKGROUND: The clinical severity in thalassaemia major (TM) depends on the underlying mutations of the beta-globin gene and the degree of iron overload. OBJECTIVE: The aim of the study was to investigate the impact of genotype on the development of endocrine complications in TM in our center. SUBJECTS AND METHODS: 126 (62 males, 64 females) thalassaemic patients of Greek Cypriot origin with a mean age of 31.2 (17-68) yr were included in the study. All patients, who were on the standard treatment protocol, were subsequently divided into two groups according to their genotype, group A (92): TM with no mitigating factor and group B (34): TM carrying one or more mitigating factors in the beta- and/or alpha-globin genes. Iron overload calculation was based on the amount of red cell consumption and the mean ferritin level over a 12-year period. Statistical analysis was performed with the SPSS program. RESULTS: Patients in group A, who were consuming larger amounts of blood on transfusions, were more likely to develop hypogonadism (P = 0.001) compared with patients in group B, despite their similar mean ferritin levels. The incidence of other endocrinopathies (short stature, hypothyroidism, and diabetes mellitus) was similar in the two groups. The prevalence of hypothyroidism in splenectomized patients was significantly higher (P = 0.005), whereas the presence of hypogonadism, impaired glucose homeostasis and insulin resistance, although more frequent, was not statistically significant. The clinical severity of TM had no impact on bone mineral density (BMD) in both men and women. BMD was only influenced by gonadal function. CONCLUSIONS: This study demonstrates that the underlying genetic defect in TM is a contributing factor for gonadal dysfunction, because the patients with the more severe defects have a greater rate of iron loading through higher red cell consumption.