Author + information
- Received February 6, 2009
- Accepted April 15, 2009
- Published online June 30, 2009.
- Rajiv D. Machado, PhD⁎,⁎ (, )
- Oliver Eickelberg, MD†,
- C. Gregory Elliott, MD‡,
- Mark W. Geraci, MD§,
- Masayuki Hanaoka, MD, PhD∥,
- James E. Loyd, MD¶,
- John H. Newman, MD¶,
- John A. Phillips III, MD#,
- Florent Soubrier, MD, PhD⁎⁎,
- Richard C. Trembath, BSc⁎ and
- Wendy K. Chung, MD, PhD††
- ↵⁎Reprint requests and correspondence:
Dr. Rajiv D. Machado, Department of Medical and Molecular Genetics, King's College London School of Medicine, 9th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, United Kingdom
Pulmonary arterial hypertension (PAH) is a rare disorder that may be hereditable (HPAH), idiopathic (IPAH), or associated with either drug-toxin exposures or other medical conditions. Familial cases have long been recognized and are usually due to mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2), or, much less commonly, 2 other members of the transforming growth factor-β superfamily, activin-like kinase-type 1 (ALK1) and endoglin (ENG), which are associated with hereditary hemorrhagic telangiectasia. In addition, approximately 20% of patients with IPAH carry mutations in BMPR2. We provide a summary of BMPR2mutations associated with HPAH, most of which are unique to each family and are presumed to result in loss of function. We review the finding of missense variants and variants of unknown significance in BMPR2in IPAH/HPAH, fenfluramine exposure, and PAH associated with congenital heart disease. Clinical testing for BMPR2mutations is available and may be offered to HPAH and IPAH patients but should be preceded by genetic counseling, since lifetime penetrance is only 10% to 20%, and there are currently no known effective preventative measures. Identification of a familial mutation can be valuable in reproductive planning and identifying family members who are not mutation carriers and thus will not require lifelong surveillance. With advances in genomic technology and with international collaborative efforts, genome-wide association studies will be conducted to identify additional genes for HPAH, genetic modifiers for BMPR2penetrance and genetic susceptibility to IPAH. In addition, collaborative studies of BMPR2mutation carriers should enable identification of environmental modifiers, biomarkers for disease development and progression, and surrogate markers for efficacy end points in clinical drug development, thereby providing an invaluable resource for trials of PAH prevention.
Funding provided by NHLBI 060056, Deseret Foundation, Intermountain Medical Center, NIH PO1 HL072058, GCRC RR000095, German Research Foundation (DFG) Collaborative Research Center 547 (to Dr. Eickelberg), the Excellence cluster “Cardiopulmonary System” (ECCPS), European Commission under the 6th Framework Programme (contract no.: LSHM-CT-2005-018725, PULMOTENSION), and BHF-FS/07/036. Please see the end of this article for each author's conflict of interest information.
- Received February 6, 2009.
- Accepted April 15, 2009.
- American College of Cardiology Foundation
- Genetic Anticipation
- The TGF-β Family and PAH
- BMPR-II Structure and Signal Transduction
- Major Genetic Risk Factors in PAH
- Mutation in BMPR2Constitutes the Primary Genetic Risk in PAH
- Truncating Mutations of BMPR2in Heritable and Idiopathic PAH
- Distribution and Impact of Missense Mutations Across Conserved Functional Domains of BMPR2
- Variants of Unknown Significance in PAH
- Rare Disease Alleles Underlying PAH
- Genetic Testing for PAH
- Clinical Monitoring of Individuals at Risk
- Reproductive Planning
- Identifying Novel, Highly Penetrant Genes for HPAH
- Genetic Modifiers of Risk for PAH
- Genome-Wide Association (GWA) Analysis in IPAH
- GWA Study Design in IPAH
- Modifiers of BMPR2Mutation in Heritable Disease
- Future Research
- Author Disclosures