title: BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension.
abstract: Mutations of the BMPR2 gene predispose to pulmonary arterial hypertension (PAH), a serious, progressive disease of the pulmonary vascular system. However, despite the fact that most PAH families are consistent with linkage to the BMPR2 locus, sequencing only identifies mutations in some 55% of familial cases and between 10% and 40% of cases without a family history (idiopathic or IPAH). We therefore conducted a systematic analysis for larger gene rearrangements in panels of both familial and idiopathic PAH cases that were negative on sequencing of coding regions. Analysis of exon dosage across the entire gene using Multiplex Ligation-dependent Probe Amplification identified nine novel rearrangements and enabled full characterization at the exon level of previously reported deletions. Overall, BMPR2 rearrangements were identified in 7 of 58 families and 6 of 126 IPAH cases, suggesting that gross rearrangements underlie around 12% of all FPAH cases and 5% of IPAH. Importantly, two deletions encompassed all functional protein domains and are predicted to result in null mutations, providing the strongest support yet that the predominant molecular mechanism for disease predisposition is haploinsufficiency. Dosage analysis should now be considered an integral of part of the molecular work-up of PAH patients.
authors.affiliation: Division of Medical Genetics, Dept. of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Micheala A
authors.initials: MA
authors.lastname: Aldred
authors.forename: Jairam
authors.initials: J
authors.lastname: Vijayakrishnan
authors.forename: Victoria
authors.initials: V
authors.lastname: James
authors.forename: Florent
authors.initials: F
authors.lastname: Soubrier
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gomez-Sanchez
authors.forename: Gunnar
authors.initials: G
authors.lastname: Martensson
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Galie
authors.forename: Alessandra
authors.initials: A
authors.lastname: Manes
authors.forename: Paul
authors.initials: P
authors.lastname: Corris
authors.forename: Gerald
authors.initials: G
authors.lastname: Simonneau
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
mesh_terms: D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D015321:Gene Rearrangement; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics*; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D011651:Pulmonary Artery / Q000473:pathology*
chemical_list: C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II