Mutations in the bone morphogenic protein receptor two (BMPR2) gene occur in approximately 80% of cases of hereditary pulmonary arterial hypertension (HPAP). Herein, we present a novel structural change in the BMPR2 gene identified by mate-pair sequencing (MPseq).
36 year old female with HPAH presented for evaluation. Family history was pertinent for a sister, mother, cousin first removed, and second cousin with HPAH. Targeted sequencing and duplicate/deletion studies, including BMPR2, did not identify a causative mutation. She underwent heart and lung transplant and a novel donor vs. recipient cell free DNA quantitative monitoring of junction sequences was used to interrogate graft health. Recipient pretransplant MPseq revealed a balanced inversion of a 5.7Mb segment of chromosome 2 with break points within intron 10 of BMPR2 and intron 6 of PIKFYVE. Additionally, MPseq was performed on her sister and maternal cousin first removed and demonstrated a synonymous mutation.
Gene mutation identification allows for informed genetic counseling regarding carrier testing prior to pregnancy, early identification of at risk family members, and in the future, may allow for gene targeted therapy. Heterozygous mutation in the BMPR2 gene is the most common mutation associated with HPAH. current screening was blind to this BMPR2 genetic variant due to the copy neutral structure of the inversion. Mate-pair sequencing is a technique that utilizes long-insert paired-end DNA libraries followed by whole genome, paired-end next generation sequencing and combines genome wide copy number analysis with nucleotide level resolution of breakpoint junctions to provide complete structural variant analysis and detection of the wide spectrum of genomic rearrangements. Thus, it allows for detection of small deletions, gains, and transposons which are not detected by standard mutational analysis. In our patient, identification of discordant fragments, indicated an inversion. We suggest that MPseq be considered in all patients with HPAH without identifiable mutation.