Introduction:

Congenital heart disease is the most common birth malformation. Pulmonary atresia is a rare type of complex cyanotic congenital heart defect mainly characterized by an undeveloped pulmonary valve or pulmonary artery, thus obstructing the blood travel from the heart to pick up oxygen from the lungs. The morbidity of the disease is 1.3% -3.4% of all congenital heart malformations with poor prognosis1. About 20% of children with pulmonary atresia with ventricular septal defect die within 2 years old2. During the fetal life, a development of prenatal ultrasound technology and a better understanding of progression of pulmonary atresia, become crucial points for the choice of lifetime of medical care including multiple surgeries or other interventions. However, ultrasound examination could not detect all potential children, especially those with major artery-pulmonary collateral arteries(MAPCAs)3. Under normal circumstances, patients do not purely suffer from PA. Usually the PA patients could combine with other heart diseases to survive. These heart diseases make it left to right shunts that make it possible for the blood to pick up oxygen from lungs through some natural passages among heart or their arteries, such as ventricular septum defect, patent ductus arteriosus and atrial septum defect. Otherwise the patients cannot survive. Accordingly, the PA is divided into two categories: pulmonary atresia with ventricular septal defect (PA/VSD) and pulmonary atresia with intact ventricular septum (PA/IVS). Among them, the ventricular septal integrity of the PA is also known as right heart dysplasia syndrome. Such patients often combine with the disappearance of the right ventricular outflow tract, resulting in a poor right ventricular development which leads to the loss of opportunities of biventricular repair4. Therefore children with PA often develop heart failure and cyanosis clinically. Presently PA is closely related to the heterozygous deletion of chromosome 22q11.2, and the range of the deletion was from 1437 Mbs to 2706 Mbs 5. The ratio of deletion mutation among the patients is about 30% to 40%. In children with PA with tetralogy of Fallot, the incidence of this heterozygous deletion is about 13%6.If the child has major artery-pulmonary collateral arteries (MAPCAs), the incidence of heterozygous deletion can be as high as 50%7.At present, the main treatment of PA is still surgery. With the rise of 3D printing technology in recent years, personalized computer modeling of children with 3D printing technology helps to improve the accuracy of the surgical procedure, while mostly reducing intraoperative radiation and contrast load, and partly assists reduce the complications it causes8,9. Although the surgical technique and perioperative management have been improved, the prognosis of PA is still poor10.Therefore, screening for children with PA in the neonatal or even fetal period through genetic or biomarker methods will greatly increase the detection rate, so that children with PA gain early diagnosis and treatment.
At present, several genetic variants have been found to be associated with the pathogenesis of PA, including chromosome copy number variation and single gene mutation. Chromosomal variation mainly includes chromosome 22q11.2 heterozygous deletion, chromosome 1q21.1 heterozygous deletion, 16p13.1, 5q14.1, 5q14.1, 10p13 duplication and 17q13.2 chromosome deletion. And the related genes located in these CNVs includes the MYH11, ABCC6, NDE1, TBX1, DHFR, PDE88, AP3B, ARSB,DMGDH, CUBN,CAMTA2, CHRNE, GP18A, ENO,GJA5 , GJA8, BCL9,etc5,11. These genes were reported to be related to the metabolism in folate and vitamin B1212,13. At the same time, several single gene mutation sites were also found, including GJA5, GJA1, GDF1, MTHFR and etc1. Bone morphogenetic protein type 2 receptor (BMPR2) is one of the transforming growth factor-β superfamily receptors, which performs diverse roles in various tissues and organs, including pulmonary vascular endothelium, pulmonary vascular smooth muscle, vasculogenesis, and osteogenesis. So far , the BMPR2 and its corresponding type 1 receptors both function in the development or differentiation of the embryos, organs and bones14. The BMPR2 consists of 1,038 amino acids, and functions within various fields such as extracellular, transmembrane, kinase, and C-terminal cytoplasmic domains15. Reports presented that the BMPR2 enhances almost every step of vascular development. Variations of the BMPR2 gene leads to various construcions and fuctions of the gene, and these changes are particularly associatied with clinical disorders including pulmonary arterial hypertension (PAH), cancers, obesity, metabolic diseases and so on15-19. BMPR2 plays important roles in various biological pathways, and to promote the vascular development, canonical BMPR2-mediated signaling cascade is reported to be associated with human microvascular endothelial cells (HMVECs), human umbilical vein endothelial cells (HUVECs), and aortic endothelial cells20.
In the present study, we collected a PA family with two affected and four unaffected members. To uncover the novel pathogenic genes or variants, we performed whole exome sequencing on six family members. With bioinformatics tools, we identified a novel variant at c.2804C>T (p. A935V) in BMPR2 as the disease-causing variant, which may function in the heart development. To our knowledge, this is the first study to report the BMPR2 as a disease-causing variant for heritable PA.