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.