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 .