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

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Puigdevall Costa, Pau, 1991-
• dc.contributor.author Piccari, Lucilla
• dc.contributor.author Blanco, Isabel
• dc.contributor.author Barberà, Joan Albert
• dc.contributor.author Geiger, Dan
• dc.contributor.author Badenas, Celia
• dc.contributor.author Milà, Montserrat
• dc.contributor.author Castelo Valdueza, Robert
• dc.contributor.author Madrigal, Irene
• dc.date.accessioned 2025-06-27T06:44:30Z
• dc.date.available 2025-06-27T06:44:30Z
• dc.date.issued 2019
• dc.description.abstract 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Puigdevall P, Piccari L, Blanco I, Barberà JA, Geiger D, Badenas C, et al. Genetic linkage analysis of a large family identifies FIGN as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension. J Med Genet. 2019;56(7):481-90. DOI: 10.1136/jmedgenet-2018-105669
• dc.identifier.doi http://dx.doi.org/10.1136/jmedgenet-2018-105669
• dc.identifier.issn 0022-2593
• dc.identifier.uri http://hdl.handle.net/10230/70769
• dc.language.iso eng
• dc.publisher BMJ Publishing Group
• dc.relation.ispartof J Med Genet. 2019;56(7):481-90
• dc.rights © Author(s). Published by BMJ Publishing Group http://dx.doi.org/10.1136/jmedgenet-2018-105669. Reuse of this manuscript version (excluding any databases, tables, diagrams, photographs and other images or illustrative material included where a another copyright owner is identified) is permitted strictly pursuant to the terms of the Creative Commons Attribution-Non Commercial 4.0 International (CC-BY-NC 4.0) https://creativecommons.org/licenses/by-nc/4.0/
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by-nc/4.0/
• dc.subject.keyword Clinical genetics
• dc.subject.keyword Genetic modifier
• dc.subject.keyword Heritable pulmonary arterial hypertension
• dc.subject.keyword Linkage
• dc.subject.keyword Reduced penetrance
• dc.title Genetic linkage analysis of a large family identifies FIGN as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion