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.