Heart Defects, Congenital, And Other Congenital Anomalies

A number sign (#) is used with this entry because of evidence that congenital heart defects and other congenital anomalies (HDCA) is caused by heterozygous mutation in the GATA6 gene (601656) on chromosome 18q11.

Clinical Features

Yorifuji et al. (1994) described a nonconsanguineous Japanese family in which the mother had undergone cardiac surgery at 19 years of age for patent ductus arteriosus and atrial septal defect. She developed diabetes mellitus after her third pregnancy at the age of 28 years. After 2 offspring were found to have hypoplasia of the pancreas, she was reexamined; abdominal CT scan showed hypoplasia of the pancreas. Only the head and the uncus of the pancreas were present; most of the body and tail were absent. The first 2 offspring of this woman had died soon after birth from unknown causes. The third child had diabetes and cyanotic congenital heart disease and died at 2 years and 8 months. Necropsy showed severe hypoplasia of the pancreas. Cardiac anomalies consisted of transposition of the great vessels, ventricular septal defects, pulmonic stenosis, and atrial septal defect. The fourth-born child had tetralogy of Fallot which was corrected surgically at the age of 6 years. At the age of 14 years, a routine school urinalysis showed glucosuria. Ultrasonographic studies of the abdomen could not identify the body of the pancreas although the splenic vein was clearly visible. Only the head and the uncus of the pancreas were demonstrated.

Balasubramanian et al. (2010) reported 3 unrelated children with pancreatic agenesis, confirmed by abdominal scan, and congenital heart defects. The first patient was a 4-year-old girl, born of nonconsanguineous parents, who developed hyperglycemia within the first 12 hours of life that required continuous insulin infusion and who also had exocrine pancreatic deficiency requiring replacement therapy. CT scan of the abdomen failed to show pancreatic tissue; on MRI, a small amount of probably hypoplastic or atrophic pancreatic tissue was seen. Echocardiography revealed a patent foramen ovale with left-to-right shunting, 1 or 2 very small apical muscular ventricular septal defects, patent ductus arteriosus with left-to-right shunt, and bilateral branch pulmonary artery stenosis. She had ongoing feeding difficulties as well as several episodes of significant liver inflammation in early childhood that spontaneously resolved. At 4 years of age, she had severe developmental delay, and cranial imaging showed focal microcalcification, gliosis, and cerebral atrophy. The second patient was a male infant, born to nonconsanguineous parents, with truncus arteriosus and large perimembranous ventricular septal defect requiring repair at 6 days of life; mechanical obstruction of pulmonary flow due to conduit ballooning led to cardiac arrest and reoperation. He was noted to have intermittent hyperglycemia requiring insulin, and was discharged at 4 months of age on daily subcutaneous insulin. By 6 months of age he was failing to thrive and had low stool elastase; abdominal MRI showed that the body of the pancreas was severely hypoplastic and the head of the pancreas was absent. At 2.5 years of age, he had microcephaly and mild to moderate developmental delay, with reduced muscle tone and feeding by gastrostomy. The third patient was a female infant born with tetralogy of Fallot who developed hyperglycemia on day 3 of life; she was found to be insulinopenic with coexisting severe exocrine pancreatic insufficiency, and required insulin and pancreatic enzyme replacement. Repeated ultrasonography failed to visualize the head of the pancreas, although the tail seemed to be present; however, the pancreas was not seen on MRI. She had a period of hyperbilirubinemia with elevated transaminases that resolved spontaneously; imaging showed a normal gallbladder and biliary tree. At 3 years of age, the patient was developmentally appropriate.

Allen et al. (2012) studied 27 individuals with pancreatic agenesis, defined as neonatal diabetes requiring insulin treatment and exocrine pancreatic insufficiency requiring enzyme replacement therapy, all born to nondiabetic parents. Complete absence of the pancreas was demonstrated in 16 (76%) of the 21 patients in whom imaging was performed; marked hypoplasia was present in the remaining 5 patients. Cardiac malformations were present in 14 (93%) of the 15 patients in whom mutations in the GATA6 gene (601656) were identified (see MOLECULAR GENETICS); in addition, 7 (47%) of the 15 mutation-positive patients had a significant neurocognitive deficit, 5 (33%) had gallbladder agenesis or biliary atresia, 5 (33%) had gut abnormalities, including diaphragmatic hernia, and 3 (20%) had additional endocrine abnormalities. Allen et al. (2012) observed that the affected individuals in whom no GATA6 mutation was detected rarely had extra-pancreatic features.

Yu et al. (2014) reported 2 families with congenital diaphragmatic hernia and cardiac anomalies. In the first family, a 3-year-old boy had left diaphragmatic hernia, tetralogy of Fallot, and a single umbilical artery. His psychomotor development was normal, and he had no history of hyperglycemia. His parents were unaffected. In the second family, the proband was a male infant with a large ventricular septal defect (VSD) who died shortly after repair of his diaphragmatic hernia due to intractable pulmonary hypertension. No dysmorphic features or other anomalies were noted. His mother had patent ductus arteriosus and congenital absence of the pericardium, and also had intestinal malrotation that was diagnosed and repaired at age 25 years. She had no history of hyperglycemia or pancreatic insufficiency. Her second pregnancy was terminated after prenatal diagnosis of left-sided diaphragmatic hernia and large VSD; autopsy showed that the fetus also had bilateral cervical ribs, absent right twelfth rib, and left ureteral duplication. In addition, although pancreatic tissue was identified in the fetus, it was noted to be ectopically located, in association with the mesentery of the small bowel.

Molecular Genetics

Allen et al. (2012) performed exome sequencing in 2 unrelated patients with pancreatic agenesis and their unaffected parents and identified heterozygosity for a de novo mutation in the GATA6 gene (601656.0006 and 601656.0007) in each proband. Subsequent analysis of GATA6 in another 24 probands with pancreatic agenesis who were negative for mutation in the PTF1A (607194) and PDX1 (600733) genes revealed 12 mutations in 13 of the probands (see, e.g., 601656.0008-601656.0011). Allen et al. (2012) noted that 14 of the 15 mutation-positive patients had congenital heart defects in addition to pancreatic agenesis and that other malformations or abnormalities were common in these patients, whereas extra-pancreatic features were rare in the 11 patients in whom no mutation was found.

In an affected female member of the Japanese family with pancreatic agenesis and congenital heart defects originally reported by Yorifuji et al. (1994), who was negative for mutation in 8 other genes associated with pancreatic development and/or function, Yorifuji et al. (2012) analyzed the GATA6 gene and identified heterozygosity for a 2-bp deletion (601656.0012). Yorifuji et al. (2012) stated that all previously reported mutations in patients with pancreatic agenesis and congenital heart defects were de novo and caused complete agenesis or pronounced hypoplasia of the pancreas. Within this family, however, the dominantly inherited mutation resulted in a variable degree of pancreatic hypoplasia and severity of diabetes among affected members ranging from neonatally lethal diabetes with only a remnant of pancreatic tissue to adult-onset diabetes associated with dorsal agenesis of the pancreas. Similar intrafamilial variability was observed with regard to the types of congenital cardiac defects present in affected individuals. The authors concluded that this observation broadened the clinical spectrum of diabetes caused by GATA6 haploinsufficiency, and noted that intrafamilial variability in phenotypic expression is relevant to the genetic counseling of such families.

By exome sequencing in 2 unrelated families with congenital diaphragmatic hernia and heart defects, Yu et al. (2014) identified heterozygous mutations in the GATA6 gene: a 3-year-old boy with left diaphragmatic hernia, tetralogy of Fallot, and a single umbilical artery had a de novo missense mutation (R456C; 601656.0008), which previously had been identified in 2 unrelated patients with congenital heart defects and pancreatic agenesis; and a male infant with a large ventricular septal defect and diaphragmatic hernia had a nonsense mutation (G238X; 601656.0013). Sanger sequencing confirmed that the mutations segregated with disease in each family. Screening for GATA6 mutations in 378 patients with congenital diaphragmatic hernia revealed 1 patient, who also had atrial septal defect, with a 1-bp deletion (601656.0014).

Exclusion Studies

In 2 children with pancreatic agenesis and congenital heart defects, Balasubramanian et al. (2010) analyzed 16 candidate genes, including the known pancreatic agenesis-associated genes PDX1 and PFT1A as well as other genes associated with permanent neonatal diabetes mellitus (see 606176), but found no mutations. In a third patient with a similar phenotype, they analyzed GATA4 (600576) and KCNJ11 (600937) but found no mutations. Paternal UPD6, 6q24 methylation aberrations, and duplications of 6q24 were excluded in all 3 patients.