Discussion

The PA disease is common complex cyanotic congenital heart disease. The etiology of PA disease is complex, and more and more studies have shown that PA is mainly related to genetic factors. In the present study, we performed whole exome sequencing on six members of the PA family to identify the disease-causing gene. Epidemiological studies have shown that the incidence of congenital heart disease in congenital malformations is 28%, and the incidence of PA is 1.3%-3.4%. In recent years, in addition to the classic MYH6, HAND1, HAND2, HEY family, etc., some new genes have been discovered. These genes control the recessive inheritance of congenital heart disease including CHD7, COL1A1, COL5A2, FBN2, NOTCH1, NSD1, and TSC2, as well as genes that only remain at animal level, such as CHD (DGCR2, DAW1, LRP1, and MYH10) and so on1. Bone morphogenetic protein (BMP) is a group of proteins that promote bone formation and act on cells such as osteoblasts, chondrocytes, and nerve cells that can affect embryonic growth and development23.BMP belongs to the multifunctional cytokine in the TGF-beta superfamily. When BMP2 binds to the cell surface threonine/serine kinase receptor, it can play a regulatory role. The TGF superfamily and related enzymes transmit signals through two types of heteropolypeptide receptors: BMPR1 (about 50-55 kD) and BMPR2 (about 70-80 kD).
In recent years, the genetic pathogenesis of PA has been confirmed by more and more studies. In 2014, Xie et al first discovered the relationship between copy number variation and PA5. These variations include 16p13.1,22q11.2,5q14.1,10p1 and 17p13.25. There are four rare pathogenic mutations leading to PA, in which repeated mutations of DHFR5q14.1 and CUBN10p13 regulate folate-mediated metabolism, MTHFR regulates the metabolism of folic acid and vitamin B12, and 17q13.2 deletion regulates CAMT2 affects NKX2.524.In 2012, Soemedi et al first proposed that the 1q21.1 mutation is a possible pathogenesis of congenital heart disease11. It was found by copy number variation analysis that most of the PA was caused by the GJA5 gene mutation. Similarly, the repetition of chromosomes such as 16p13.1, 5q14.1, 5q14.1, and 10p13 and the deletion of the 17q13.2 chromosome may also result in PA25.Single gene locus research, in recent years, found that GJA5, GJA1, GDF1, MTHFR, etc. 7,26. may be related to the pathogenesis of PA. In 1995, Rosenzweig et al first discovered that transfected COS-1 cells, BMP7, and BMP4 (112262) were linked to BMPR227.And the chemical bonds between these connections are only stable in the presence of BMPR1. Most studies have found that mutations in the BMPR2 gene located on chromosome 2q33 are associated with the pathogenesis of most diseases, including familial pulmonary hypertension (PAH) and pulmonary veno-occlusive disease (PVOD)28. Certain deletions of the BMPR2 gene have been shown to trigger atherosclerosis in animal experiments29. Also included are some of the diseases caused by genes that interact with BMPR2: the Prader-Willi syndrome caused by the action of NIPA130.
In this study, we performed a complete exome sequencing, bioinformatics analysis and Sanger sequencing in a family of PA families inherited from three generations. It was found that the unreported new mutations in the BMPR2 gene may be related to the pathogenesis of PA in this family. This family is the genetic basis of the pathogenesis of PA, increasing the genetic profile of PA. It has been shown that BMPR2 prominently expressed in the vascular development and is associated with canonical WNT signaling pathway. And other than PA, the mutation could also lead to typical cardiovascular diseases such as PAH as well as obesity31. Both the proband and the proband’s brother develop the disease, and the proband’s mother who carrys the mutation of the gene also presents typical symptoms including obesity and other cardiovascular disease symptoms.
The study of these genes is either in the screening or screening stage, or in the animal experiment stage, but the correlation between them and the pathogenesis of PA is still unclear32313030 29. This study is to verify the pathogenesis of PA by performing full exome sequencing and candidate mutation family members in a PA family member. In this study, we performed high-throughput second-generation sequencing technology for whole exome sequencing of patient samples. Whole exome sequencing uses target sequence capture technology to capture high-throughput DNA from all exome regions of the genome, which not only can quickly detect the pathogenic genes of rare genetic diseases, but also can be used for common diseases caused by multiple genes. Thereby revealing the genetic pathogenesis of these diseases.
In summary, the clinical manifestations, diagnostic criteria and treatment options of PA are relatively clear, and the concept that genetic factors play an important role in the pathogenesis of PA is also recognized by most clinicians and researchers. Gene mutations are associated with the pathogenesis of PA. But the pathogenesis of PA is still unclear. This study found in a PA family that BMP signaling pathway is possibly associated with the cardiac development and confirmed that mutations in this gene may be closely related to the pathogenesis of PA in this family. However, it is also necessary to verify the overall prevalence of mutations in the BMPR2 gene in the PA population in a large number of PA sporadic cases and PA families. Further in vivo and in vitro experiments are needed to determine whether the mutation does lead to the pathogenesis of PA and its pathogenesis, and elucidate the association between genotype-phenotype. At the same time, this study also suggests that the BMP family may be one of the important signaling molecules involved in the pathogenesis of PA. BMP signaling pathway may be one of the breakthroughs in the pathogenesis of PA.