Abstract 14413: Whole Genome Sequencing in Idiopathic and Familial Pulmonary Arterial Hypertension Reveals Causal Rare Coding and Non-coding Sequence Variation
Introduction: Molecular genetic analyses of individuals with pulmonary arterial hypertension (PAH) have identified rare pathogenic variation in several genes, including BMPR2, ACVRL1, ENG, CAV1, SMAD1, SMAD4, SMAD9, KCNK3, and EIF2AK4. Whilst mutations in BMPR2 remain the most frequent genetic cause of PAH, a large proportion of cases with heritable (~20%) and idiopathic PAH (~80%) still remain unexplained at the molecular level.
Hypothesis: Sequencing the entire genomes of a large case-control cohort identifies missing causal protein-coding and non-coding variation contributing to this disease.
Methods: As part of the UK 10,000 Genomes BRIDGE project the whole genomes of up to 1,250 unrelated individuals diagnosed with idiopathic and familial PAH are being sequenced. Reads are aligned and variants are called using Illumina’s pipeline. Stringent filtering based on minor allele frequency (MAF < 1/10,000) in both BRIDGE disease controls and ExAC, and the combined annotation dependent depletion deleteriousness score (CADD > 15) are used to prioritise pathogenic variants. The filtered variants are subsequently tested for association with phenotype data and clinical information.
Results: To date 6687 whole genomes of rare disease patients have been sequenced including 781 PAH cases. 137 PAH subjects (18%) possess clearly or likely pathogenic mutations in one of the known PAH genes. The majority of loss-of-function and likely pathogenic missense mutations have been identified in BMPR2 (95 PAH cases [12%]). Further 18 subjects had (micro-)deletions of 5kb to 3.8Mb affecting either the entire BMPR2 locus or one or more exons within the gene. Additional variants in the promoter and other non-coding regions of BMPR2 are undergoing functional investigation. Unexpectedly, we also identified a larger number of individuals with homozygous (n=7) and potential compound heterozygous (n=6) variants in EIF2AK4 (2%). BMPR2 and EIF2AK4 mutation carriers present at younger age.
Conclusions: Of the known PAH genes, BMPR2 mutations are the most common followed by EIF2AK4. It is likely that non-coding variation around known PAH genes, in particular BMPR2, will explain further PAH cases. An even larger sample size will be needed for novel rare sequence variation association.
Author Disclosures: S. Gräf: None. M. Bleda: None. C. Haddinapola: None. M. Haimel: None. H.J. Bogaard: None. G. Coglan: None. P.A. Corris: None. J.S. Gibbs: None. M. Humbert: None. D.G. Kiely: None. A. Laurie: None. R.D. Machado: None. A.J. Peacock: None. J. Pepke-Zaba: None. M. Toshner: None. R.C. Trembath: None. A. Vonk Noordegraaf: None. J. Wharton: None. M. Wilkins: None. S.J. Wort: None. N.W. Morrell: None.
- © 2016 by American Heart Association, Inc.