Abstract 18033: Whole Exome Sequencing Identifies Novel Candidate Genes in a Cohort of Patients with Idiopathic Pulmonary Arterial Hypertension
Introduction: Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disorder characterized by elevated pulmonary pressures and chronic right heart failure. Genetic studies have identified mutations in the bone morphogenetic protein receptor (BMPR) 2 in ±80% of familial and ±25% of IPAH cases. However, given the low penetrance (±20%) of BMPR2 mutations, other genetic modifiers may be necessary for disease development. Next generation sequencing techniques such as whole exome sequencing (WES) can help discover potentially deleterious gene mutations in protein coding regions of the genome and accelerate the discovery of causative genes in both mendelian and complex trait disorders. We proposed that WES in a cohort of IPAH patients would lead to the discovery of novel gene candidates potentially relevant to IPAH pathobiology.
Methods: We isolated genomic DNA from buffy coat of 12 unrelated patients with IPAH and performed WES using the Illumina HiSeq 2000 sequencer. Exome sequences were aligned to the UCSC Hg19 reference genome followed by annotation of single nucleotide polymorphisms, insertions/deletions and translocations using ANNOVAR. Prediction of deleteriousness in all discovered variants was performed using SIFT, polyphen, mutation taster, phyloP, GERP++ and LRP algorithms.
Results: A total of 226,864 variants were screened for synonymous and benign variants resulting in 2,115 genes of interest. Priority was given to those genes with a minor allele frequency (MAF) of <1%. Prediction algorithms identified high risk mutations in genes involved in the BMP signaling (BMP8A and TOPBP1), vesicular trafficking (SIGLEC1, SEC23B, FKTN), extracellular matrix (SSX2IP, VCAN), cell cycle (CCNH, PRKDC, MAP4, MYSM1), immune response (FCER2 and 3) and cell growth (NRG1, CTCFl, NBEAL2). Since mutations in PRKDC, MAP4, VCAN and NRG1 have previously been linked to systemic cardiovascular disease, it is possible that one or more of these genes could be acting as disease modifiers in IPAH.
Conclusion: WES has facilitated the discovery of new genes potentially involved in IPAH pathogenesis. Future studies will characterize their functional relevance in regulation of disease development and response to therapy.
- © 2012 by American Heart Association, Inc.