Cardiac Valvular Defect, Developmental

A number sign (#) is used with this entry because of evidence that developmental cardiac valvular defects (CVDD) can be caused by homozygous or compound heterozygous mutation in the PLD1 gene (602382) on chromosome 3q26.

Clinical Features

Bendon et al. (1987) described a male infant (family B) who died at age 2.5 months after surgery for replacement of the mitral valve for mitral stenosis. Tricuspid regurgitation was also present and both atrioventricular valves were thickened. The infant also had nonobstructive right hydronephrosis and hydroureter and a urethral diverticulum. At the age of 2 months he had undergone bilateral inguinal herniorrhaphies prompted by an incarcerated inguinal hernia. The mother of the patient had earlier had a first-trimester spontaneous abortion. A third pregnancy resulted in an induced delivery of a dead male infant at 24 weeks of gestation. Thickening of the atrioventricular valves was found. In a fourth pregnancy, fetal hydrops was detected ultrasonographically at 22 weeks and fetal death at 25 weeks. The fetus showed thickened tricuspid leaflets that were partially bound to the wall below the annulus, and irregular thickening of the mitral valve with a parachute configuration.

Ta-Shma et al. (2017) studied 2 unrelated consanguineous families in which 6 individuals were born with cardiac valvular defects. In family A, there were 2 affected brothers, aged 23 years and 17 years: the older brother had severe subvalvular pulmonary stenosis, moderately hypoplastic right ventricle (RV), 3 medium-sized ventricular septal defects (VSDs), and a large atrial septal defect, whereas the younger brother had tricuspid and pulmonary atresia, single left ventricle, and small pulmonary arteries. After being lost to follow-up, the older brother presented at age 22 years with central cyanosis; at surgery, hypertrophy of the RV with absence of the RV outflow tract infundibulum and pathologic attachment of the septal leaflet of the tricuspid valve to the RV free wall were observed. An older sister in family A had died at age 1 year with a massive muscular VSD and severe subpulmonic and valvular pulmonic stenosis. In family B, a 2-year-old girl had severe mitral regurgitation (MR) with progressive left atrial and ventricular dilation, which worsened the MR. At mitral valve repair, elongation of the chordae was found. A 17-year-old male second cousin was born with mild cyanosis, at which time echocardiography showed mild tricuspid and pulmonic stenosis, mildly hypoplastic RV, mild MR, and patent foramen ovale. At 1 month of age, he was tachypneic with mild to moderate MR and dilated left atrium, which improved with diuretics. His sister, who was born with severe cyanosis and died at 21 days of life, had tricuspid and pulmonary atresia, VSD, hypoplastic RV, small pulmonary arteries,and left aortic arch with aberrant right subclavian artery. None of the patients exhibited extracardiac symptoms or dysmorphism.

Molecular Genetics

By whole-exome sequencing in 11 families with congenital cardiac valvular defects, Ta-Shma et al. (2017) identified homozygosity for a missense mutation in the PLD1 gene (H442P; 602382.0001) in 2 affected brothers (family A). In another family (family B), a 2-year-old affected girl was homozygous for a 2-bp deletion (602382.0002) in the PLD1 gene, whereas her affected second cousin was compound heterozygous for the 2-bp deletion and a splice site mutation (602382.0003). The mutations segregated fully with disease in each family and were not found in the ExAC database.