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Genetic Analysis of 2,592 WHO Group 1 PAH Patients Enrolled in the PAH Biobank

Katie Lutz

Anna Walsworth

Michael Pauciulo

Lisa Martin

H He

William Nichols


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Conference: 2018 PHA International PH Conference & Scientific Sessions

Release Date: 07.28.2018

Presentation Type: Abstracts

File Download: Conference 2018_1002

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2018 International PH Conference and Scientific SeAbstract presented at the 2018 International PH Conference and Scientific Sessions in Orlando, Fla., June 28-July 1, 2018.


The National Biological Sample and Data Repository for PAH (PAH Biobank) was established with NHLBI funding to build a resource of biological specimens, clinical data and genetic data available to the PAH research community to further our understanding of the pathogenesis of this potentially fatal disease. Information on the resource and access to the samples/ data can be found at To date, 2,851 patients have been enrolled from 38 Enrolling Centers.


Blood samples are collected at the Enrolling Centers across the U.S and shipped overnight to the PAH Biobank. Blood is processed to store plasma and serum, extract DNA and RNA, and prepare immortalized cell lines. DNA sequencing is performed using the Illumina TruSeq Custom Amplicon system to interrogate the coding sequences/intron-exon junctions of BMPR2, ALK1, ENG, CAV1, SMAD9, KCNK3, EIF2AK4, ABCC8, GDF2, KCNK5, SMAD4 and TBX4. Genotyping of >4.3 million SNPs is done using the Illumina HumanOmni5 Beadchip. Multiplex ligation-dependent probe amplification is performed to identify exonic deletions/duplications of BMPR2, ALK1, and ENG.


Genetic analysis has been completed in 2,592 patients including 1130 IPAH, 1,231 APAH, 101 FPAH, and 116 Drugs and Toxins PAH. 695 distinct variants occurred 24,425 times. 294 distinct synonymous and intronic variants occurred 19,542 times. The remaining 401 coding variants were observed 4,883 times. This included 33 nonsense variants in 57 patients, 70 ins/dels in 504 patients, and 14 splice site variants in 18 patients. 284 missense variants occurred 4,304 times; some patients harbored more than one missense variant. Of the 401 distinct coding variants, 141 were in BMPR2. The remaining 260 coding variants were spread across ALK1 (35), ENG (34), CAV1 (9), SMAD9 (27), KCNK3 (9), EIF2AK4 (69), ABCC8 (18), GDF2 (22), KCNK5 (19) SMAD4 (4) and TBX4 (14). MLPA identified 21 exonic insertion/deletions in BMPR2 (19), ALK1 (1) and ENG (1) in 11 IPAH, 8 HPAH, and 2 APAH patients.


The PAH Biobank is a powerful resource available to the PAH research community. This is the largest single cohort for which genetic analysis has been completed to date. While pathogenic/suspected pathogenic variants have been identified in several genes, BMPR2 remains the gene with the most pathogenic/suspected pathogenic variants. Stratification of the cohort based on these genetic analyses could enable the identification of additional, novel genes and/or modifier genes affecting disease severity/penetrance in those harboring pathogenic/suspected pathogenic variants in previously identified genes.