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.

Emotional and behavioral problems in children with dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) in children is an important cause of severe heart failure and carries a poor prognosis. Adults with heart failure are at increased risk of anxiety and depression and such symptoms predict adverse clinical outcomes such as mortality. In children with DCM, studies examining these associations are scarce. AIMS: We studied whether in children with DCM: (1) the level of emotional and behavioral problems was increased as compared to normative data, and (2) depressive and anxiety problems were associated with the combined risk of death or cardiac transplantation. METHODS: To assess emotional and behavioral problems in children with DCM, parents of 68 children, aged 1.5-18 years (6.9±5.7 years), completed the Child Behavior Checklist. RESULTS: Compared to normative data, more young children (1.5-5 years) with DCM had somatic complaints (24.3% vs. 8.0%; p < .001), but fewer had externalizing problems (5.4% vs. 17.0%; p = .049). Overall internalizing problems did not reach significance. Compared to normative data, more older children (6-18 years) showed internalizing problems (38.7% vs. 17.0%; p = .001), including depressive (29.0% vs. 8.0%; p < .001) and anxiety problems (19.4% vs. 8.0%; p = .023), and somatic complaints (29.0% vs. 8.0%; p < .001). Anxiety and depressive problems, corrected for heart failure severity, did not predict the risk of death or cardiac transplantation. CONCLUSION: Children of 6 years and older showed more depressive and anxiety problems than the normative population. Moreover, in both age groups, somatic problems were common. No association with outcome could be demonstrated.

Response profiles of oxygen uptake efficiency during exercise in healthy children.

BACKGROUND: Oxygen uptake efficiency (OUE), the relation between oxygen uptake (VO2) and minute ventilation (VE), differs between healthy children and children with heart disease. This study aimed to investigate the normal response profiles of OUE during a progressive cardiopulmonary exercise test. DESIGN: Cross-sectional. METHODS: Healthy children between eight and 19 years of age (114 boys and 100 girls, mean ± SD age 12.7 ± 2.8 years) performed a maximal cardiopulmonary exercise test. Peak VO2 (VO2peak), ventilatory threshold and peak VE were determined. OUE was determined by the OUE plateau (OUEP), OUE at the ventilatory threshold (OUE@VT) and OUE slope (OUES). RESULTS: OUEP (42.4 ± 4.6) and OUE@VT (41.9 ± 4.7) were similar and less variable than OUES (2138 ± 703). OUEP correlated strongly with OUE@VT (r = 0.974); however, OUEP was weak-to-moderately correlated with VO2peak (r = 0.646), the ventilatory threshold (r = 0.548) and OUES (r = 0.589). OUES correlated strongly with VO2peak (r = 0.948) and the ventilatory threshold (r = 0.856). Reference centiles for OUEP show an almost linear increase from about 37 in eight-year olds to about 47 in 18-year olds, with no sex-difference. OUES increased from about 1400 in eight-year-old boys to approximately 3500 in 18-year-old boys. OUES increased from roughly 1250 in eight-year-old girls to about 2650 in 18-year-old girls. CONCLUSIONS: This study provides sex- and age-related normative values for both OUEP and OUES, which facilitates the interpretation of OUE in children. OUEP and OUES are objective and non-invasive cardiopulmonary exercise test parameters which do not require a maximal effort and might be indicative of cardiorespiratory function during exercise.