EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD0001000163332EGA dataset EGAD00010001633EGA<h4>Background</h4>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 (<i>BMPR2</i>) 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 <i>BMPR2</i> mutation c.1472G>A (p.Arg491Gln), 8 of them diagnosed with PAH by right-heart catheterisation, leading to an RP rate of 36.4%.<h4>Methods</h4>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.<h4>Results</h4>We identified a candidate chromosome region in 2q24.3, 38 Mb upstream from <i>BMPR2</i>, 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 (<i>FIGN</i>) gene.<h4>Conclusion</h4>Our results suggest that the genetic modifier acts through <i>FIGN</i> 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 <i>BMPR2</i>.Genetic linkage analysis of a large family identifies <i>FIGN</i> as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension.Puigdevall Pau P, Piccari Lucilla L, Blanco Isabel I, Barberà Joan Albert JA, Geiger Dan D, Badenas Celia C, Milà Montserrat M, Castelo Robert R, Madrigal Irene IFPAH, 7-dioic acid hydratase activity, 2-oxo-hepta-3-ene-1, HPAH., 7-dioate hydratase activity, familial pulmonary arterial hypertension, hereditary pulmonary arterial hypertension, HpaHNetworks, HPAH., Family Member, Kinship Network, Kinship, Family Research, Research, HpaH, FPAH, Network, 7-dioic acid hydratase activity, Family Members, Life Cycles, familial pulmonary arterial hypertension, hereditary pulmonary arterial hypertension, Families, 2-oxo-hepta-3-ene-1, Life Cycle, Kinship Networks, Family Life Cycles, 7-dioate hydratase activity, Family, Filiation, Relatives, Family Life Cyclesmall, Networks, Family Member, Kinship, Family Research, Dexfenfluramine-Associated, gyltl1b-b, acetylglucosaminyltransferase-like protein, Fenfluramine-Associated, Genetic Linkage Analyses, HpaH, Mbp1, Linkage Analysis, Network, Primary, Linkage Analyses, Idiopathic Pulmonary Hypertension, LARGE1, froggy, Gyltl1a, Family Members, Idiopathic Pulmonary Arterial Hypertension., reduced, familial pulmonary arterial hypertension, hereditary pulmonary arterial hypertension, MDDGA6, mKIAA0609, Pph1 With Hht, Genetic Linkage Analysis, fidget, 1, Life Cycle, Analysis, tiny, KIAA0609, myd, Filiation, acetylglucosaminyltransferase-like 1A, Family Life Cycle, fg, fi, gyltl1b, Genetic, Kinship Network, like-acetylglucosaminyltransferase, Analyses, underdeveloped, Research, MDDGB6, FPAH, mdc1d, hypoplasia, Mbp-1, LARGE, Pulmonary Hypertension, LARGE_HUMAN, Idiopathic Pulmonary, Genetic Linkage, Hypertension, With Hereditary Hemorrhagic Telangiectasia, BPFD#36, Life Cycles, Heritable Pulmonary Arterial Hypertension, Linkage, MDC1D, Idiopathic, like-glycosyltransferase, enr, Families, Primary Pulmonary Hypertension, Kinship Networks, Family Life Cycles, Family, Primary Pulmonary, Relatives, glycosyltransferase-like protein LARGE1Networks, MGC130048, bmprii, Materials, Herz, Kinship, l(3)LG9, determination, BMP-2, acetylglucosaminyltransferase-like protein, Sry-rDM33, Mbp1, A4, Sry-rDM36, adult heart, Social Controls, Mutations, Techniques, Readability, diseases, Method, 1.14.16.1, BMPR-II, AA959943, 1, Sry-rDM23, T-ALK, Life Cycle, diseases and disorders, myd, Fs(3)Hor, Formal Social Controls, Family Life Cycle, Morphogenetic Protein, gamma sarcoglycan, human disease, DmelCG2684, Kinship Network, DM10, like-acetylglucosaminyltransferase, Comparative Genomics, FPAH, hypoplasia, L-lysine:oxygen 6-oxidoreductase (deaminating) activity, AW106920, bu, Mbp-1, BB189135, procedures, cardiac structure, NTef2, Pulmonary Hypertension, Idiopathic Pulmonary Arterial Hypertension, Acts, Sry-rDM10, genetic, Social, geographical area, POVD1, Methodological Studies, BMPRII, gamma-sarcoglycan, Homo sapiens disease, PAH, Pah, Family Life Cycles, fish, Sox70D, Diagnostic Findings, Acta-2, SIGNS SYMPTOMS, Genomics, Dexfenfluramine-Associated, DM33, gyltl1b-b, DM36, Comparative, DESC, familial, SG-gamma, Actsk-1, pah, Functional Genomics, Procedure, Idiopathic Pulmonary Hypertension, brk-3, Haplotype, predicted, Fs(3)Sz11, DTPH, hereditary pulmonary arterial hypertension, DM23, MDDGA6, Morphogenetic Proteins, mKIAA0609, Genetic Materials, sarcoglycan, cardium, KIAA0609, Filiation, Genetic Material, acetylglucosaminyltransferase-like 1A, Sry-rDM63, t-alk, Phe-4-monooxygenase, fg, fi, gyltl1b, positional polypeptide feature, PPH1, mdc1d, Control, INSDC_feature:gene, Methodological, Controls, proclavaminate amidino hydrolase activity, gamma (35kDa dystrophin-associated glycoprotein), LARGE_HUMAN, Methodological Study, chromosome region, t-alk., early, Hypertension, With Hereditary Hemorrhagic Telangiectasia, Life Cycles, disease, MDC1D, AW546137, DMDA, enr, Material, 35kD dystrophin-associated glycoprotein, Horka, Primary Pulmonary Hypertension, BMPR-2, CG2684, Fs(3)Horka, Cistron, inherited genetic, disease characteristic, proclavaminic acid amidino hydrolase activity, Gm20272, Bmpr-II, Regulation, Clinical Finding, Bone, pph1, Regulations, other disease, SOXB2.1, SGCG_HUMAN, Family Member, Procedures, region or site annotation, Fenfluramine-Associated, HpaH, Gene, branchial heart, Network, LARGE1, TYPE, froggy, Symptoms and Signs, Gyltl1a, Human, Lod, loD, DAGA4, DM63, Structural, reduced, BRK-3, 35DAG, Studies, Functional, disease or disorder, DmF2, tiny, CG7399, qualifier, CG5893, Finding, MAM, gamma-SG, SCG3, Technique, lod, positional, Genetic, Research, TPH, Tph, MDDGB6, LARGE, PVOD/PCH, Idiopathic Pulmonary, non-neoplastic, Study, Heritable Pulmonary Arterial Hypertension, BPFD#36, LodA, Idiopathic, disorder, Kinship Networks, constitutitional genetic, Family, small, BMPR3, DmelCG5893, DmelCG7399, Sox B2-1, modifier, Family Research, 35 kDa dystrophin-associated glycoprotein, TRH, Trh, Formal Social Control, marinocine, Sox70, disorders, PKU1, medical condition, Primary, Hearts, Genetics, Qualifier, Cistrons, Bone Morphogenetic Protein, SGCG, LGMD2C, AL117858, Family Members, Signs and Symptoms, bmr2, familial pulmonary arterial hypertension, Social Control, SOX70D, Pph1 With Hht, chemical analysis, sequence, fidget, condition, BMR2, techniques, PKU, INSDC_feature:regulatory, SOXDP, 2610024H22Rik, disease qualifier, PAH with overt features of venous/capillaries involvement, DMDA1, underdeveloped, L-lysine-epsilon-oxidase activity, Understanding, Lds, Modifier, primary structure of sequence macromolecule, bmpr3, bmpr-ii, SOX70, xbmpr-ii, like-glycosyltransferase, Families, SCARMD2, Structural Genomics, regulation, assay, PH, Primary Pulmonary, hereditary, Relatives, glycosyltransferase-like protein LARGE1, methodologyfalseHPAH Genotyping dataGenotyping data for 32 individuals from a family affected by HPAH2018-12-04 12:51:54EGAD00010001633960630894412EGAC00001001057EGAS00001003123