Genetic linkage analysis of a large family identifies as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension.

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 () 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 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 , 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 () gene.

Conclusion: Our results suggest that the genetic modifier acts through 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 .