Genetics and genomics of pulmonary arterial hypertension.
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-beta 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 BMPR2 mutations 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 BMPR2 in IPAH/HPAH, fenfluramine exposure, and PAH associated with congenital heart disease. Clinical testing for BMPR2 mutations 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 BMPR2 penetrance and genetic susceptibility to IPAH. In addition, collaborative studies of BMPR2 mutation 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.
Machado
Rajiv D
RD
Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, United Kingdom. Electronic address: rajiv.machado@genetics.kcl.ac.uk.
Eickelberg
Oliver
O
Comprehensive Pneumology Center, Ludwig-Maximilians-Universität, Asklepios Klinik Gauting und Helmholtz Zentrum München, and Institute of Lung Biology and Disease (iLBD), Helmholtz Zentrum München, Munich, Germany.
Elliott
C Gregory
CG
Departments of Medicine, Intermountain Medical Center and the University of Utah School of Medicine, Salt Lake City, Utah.
Geraci
Mark W
MW
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado.
Hanaoka
Masayuki
M
First Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Loyd
James E
JE
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
Newman
John H
JH
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
Phillips
John A
JA
Department of Pediatrics and Division of Medical Genetics, Vanderbilt University School of Medicine, Nashville, Tennessee.
Soubrier
Florent
F
Faculté de Medicine, Université Paris 6, Hôpital Pitié-Salpêtrière, Paris, France.
Trembath
Richard C
RC
Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.
Chung
Wendy K
WK
Departments of Pediatrics and Medicine, Columbia University College of Physicians & Surgeons, New York, New York.
D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics; D016368:Frameshift Mutation / Q000235:genetics; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology
D016212:Transforming Growth Factor beta; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II