918: Variable phenotypic presentation of PLD1 associated congenial heart disease in a set of identical triplets

Abstract

To investigate the underlying etiology of three variable phenotypic congenital heart defects (CHD) in a set of identical triplets. The initial diagnosis of fetal CHD was made during an anatomy scan performed at 20 weeks and 2 days of gestation. Further analysis of the triplet hearts were performed via interval echocardiograms throughout the pregnancy. Post-natal evaluations included neonatal echocardiograms and familial microarray comparative genomic hybridization (aCGH) assays and next generation sequencing (NGS) gene panels. Final diagnoses of cardiac status of infant A: patent foramen ovale; infant B: bicuspid pulmonary valve, pulmonary stenosis, ventricular septal defect, atrial septal defect, and bilateral superior vena cava without evidence of bridge; infant C: functional single ventricle (tricuspid atresia, absent pulmonary valve, right ventricle hypoplasia due to right ventricular septal mass, left ventricle non compaction cardiomyopathy), dual atrioventricular node physiology, and multi-factorial pulmonary hypertension. Postnatal aCGH and NGS were performed on all family members. This allowed for the detection of compound heterozygous changes in the PLD1 gene in all three of the infants. The mother was heterozygous for the missense mutation, c.3142C>G on chromosome 3 in the region of the PLD1 gene. The father was heterozygous for a partial duplication of exon 12-19 in the PLD1 gene. All three infants were found to have compound heterozygous mutations of PLD1, including a partial duplication and a missense mutation. While PLD1 pathogenic variants have been associated with cardiac changes mainly in the valves, this report shows that the same genetic changes in identical siblings can have a dramatic variation in phenotype. It also reveals a new association between left ventricular non-compaction and the PLD1 gene.View Large Image Figure ViewerDownload Hi-res image Download (PPT)