Whole Exome Sequencing Identifies A Novel Pathogenic Bmpr2 Variant in Pulmonary Atresia

Abstract

Objective: Pulmonary atresia (PA) is a rare type of complex cyanotic congenital heart defect characterized primarily by an undeveloped pulmonary valve or pulmonary artery. Therefore, defining a disease-causing gene mutation in a pulmonary atresia family is a possible method of genetic counseling, future prenatal diagnosis, and therapeutic approaches for pulmonary atresia. Methods: Blood samples were collected from six PA family members, and genomic DNA was extracted using the QIAamp DNA Blood Mini Kit. Gene detection was performed using a second-generation sequencing gene panel. Results: Genetic testing results indicated that a heterozygous mutation originating from maternal inheritance was detected in the BMPR2 gene of the proband's genomic DNA. The pathogenic gene was c.2804C>T (p. A935V). The mutation was also detected in the genomic DNA of the proband's elder brother (III-1), but not in other family members. Conclusion: To the best of our knowledge, this is the first study to report the BMPR2 variant responsible for pulmonary atresia. The frequency of the c.2804C>T (p. A935V) mutation detected in this family is extremely low in the normal population (1/246048). The mutation was highly conserved among different species. Sorting intolerant from tolerant (SIFT) predicts it to be a harmful mutation.