Background Mapping the genetic component of molecular mechanisms responsible for the reduced penetrance (RP) of rare disorders constitutes one of the most challenging problems in human genetics. Heritable pulmonary arterial hypertension (PAH) is one such disorder characterised by rare mutations mostly occurring in the bone morphogenetic protein receptor type 2 (BMPR2) gene and a wide heterogeneity of penetrance modifier mechanisms. Here, we analyse 32 genotyped individuals from a large Iberian family of 65 members, including 22 carriers of the pathogenic BMPR2 mutation c.1472G>A (p.Arg491Gln), 8 of them diagnosed with PAH by right-heart catheterisation, leading to an RP rate of 36.4%.
Methods We performed a linkage analysis on the genotyping data to search for genetic modifiers of penetrance. Using functional genomics data, we characterised the candidate region identified by linkage analysis. We also predicted the haplotype segregation within the family.
Results We identified a candidate chromosome region in 2q24.3, 38 Mb upstream from BMPR2, with significant linkage (LOD=4.09) under a PAH susceptibility model. This region contains common variants associated with vascular aetiology and shows functional evidence that the putative genetic modifier is located in the upstream distal promoter of the fidgetin (FIGN) gene.
Conclusion Our results suggest that the genetic modifier acts through FIGN transcriptional regulation, whose expression variability would contribute to modulating heritable PAH. This finding may help to advance our understanding of RP in PAH across families sharing the p.Arg491Gln pathogenic mutation in BMPR2.
- clinical genetics
- reduced penetrance
- heritable pulmonary arterial hypertension
- genetic modifier
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Contributors IM, MM, CB and RC designed the project. IM, MM, CB, LP, IB and JAB collected the data. PP, DG and RC analysed the data. PP, CB, IM, LP and RC drafted the manuscript. All authors revised and approved the manuscript.
Funding This work was supported by the Spanish Instituto de Salud Carlos III (ISCIII) [PI15/00483], co-financed by Fondo Europeo de Desarrollo Regional (FEDER) ’una manera de hacer Europa', Catalan AGAUR [SGR17-1134; SGR17-1020; FI-DGR 2015], Spanish MINECO/FEDER (TIN2015-71079-P) and the ‘Maria de Maeztu Unit of Excellence’ (MDM-2014-0370). The ‘CIBER de Enfermedades Raras’ is an initiative of the ISCIII. We want to thank the “CERCA Programme” from the Autonomous Catalan Government.
Competing interests None declared.
Ethics approval The study was approved by the ethical committee of the Hospital Clínic de Barcelona. All participants provided written, informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Genotype and phenotype data reported in this paper are available through the European Genome-phenome Archive (EGA) under accession number EGAS00001003123.
Correction notice This article has been corrected since it was published online first. A technical error in the PDF (figure 3 was not displaying) has been corrected.
Patient consent for publication Not required.
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