2 Results

In this study, 2 cases of PA patients and other family members without PA in the family were subjected to full exome sequencing analysis. Firstly, standard karyotype on these family members revealed a normal 46,XY karyotype. Then the array-CGH performed on the proband with PA did not show any chromosomal imbalance. The original sequencing sequences obtained by sequencing of each sample were finely filtered and then subjected to subsequent bioinformatics analysis. The target area coverage was 99.41%, average coverage depth >20x. The whole exome capture was successful and the sequencing quality was reliable. Two cases of PA and the proband’s mother who was considered to be a carrier of the mutated gene shared the mutant gene. And the variation that the proband’s sister who is considered as a normal control does not have. Therefore, the mutant gene was considered as a candidate gene mutation. In order to refine our list of mutations, we finally screened for mutations that were predicted to be functionally harmful by SIFT and CADD, and which were not reported in any database. The score of CADD was 22.8. according to the guidelines for genetic variant interpretations(ACMG) by Richards et al., the mutation was variant uncertain significance (VUS).But in this family, both the two children gained the disease, and the mother who carries the mutation develop cardiovascular diseases symptoms. Furthermore, only one mutation was found in this family associated with this disease. Our test identified a novel homozygous missense variant c.2804C>T (p. A935V) in BMPR2.Moreover, the changes of construcions of the gene were proved to be associated with pulmonary diseases such as PAH, so in our opinion, the mutation was accosiated with the disease.
Whole exome sequencing results demonstrate that BMPR2 gene mutation may be related to the pathogenesis of PA. A heterozygous mutation in the BMPR2 gene c.2804C>T (p. A935V) was rarely found in the normal database gnomAD (1/246048). Mutation of BMPR2 in the blood samples of the two cases of PA and the proband’s mother who was considered to be a carrier of the mutated gene was found. And no mutation of BMPR2 in the blood samples of other family members in this family were treated as normal controls. The mutation was presented in Figure 3 .