Association of modifiers and other genetic factors explain Marfan syndrome clinical variability

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Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder related to variants in the FBN1 gene. Prognosis is related to aortic risk of dissection following aneurysm. MFS clinical variability is notable, for age of onset as well as severity and number of clinical manifestations. To identify genetic modifiers, we combined genome-wide approaches in 1070 clinically well-characterized FBN1 disease-causing variant carriers: (1) an FBN1 eQTL analysis in 80 fibroblasts of FBN1 stop variant carriers, (2) a linkage analysis, (3) a kinship matrix association study in 14 clinically concordant and discordant sib-pairs, (4) a genome-wide association study and (5) a whole exome sequencing in 98 extreme phenotype samples.

Three genetic mechanisms of variability were found. A new genotype/phenotype correlation with an excess of loss-of-cysteine variants (P = 0.004) in severely affected subjects. A second pathogenic event in another thoracic aortic aneurysm gene or the COL4A1 gene (known to be involved in cerebral aneurysm) was found in nine individuals. A polygenic model involving at least nine modifier loci (named gMod-M1-9) was observed through cross-mapping of results. Notably, gMod-M2 which co-localizes with PRKG1, in which activating variants have already been described in thoracic aortic aneurysm, and gMod-M3 co-localized with a metalloprotease (proteins of extra-cellular matrix regulation) cluster. Our results represent a major advance in understanding the complex genetic architecture of MFS and provide the first steps toward prediction of clinical evolution.

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This work was supported by DHU FIRE (Emergence 2 project for MA), Programme Hospitalier de Recherche Clinique (CRC07032 and P071009 for CS, AOM10108 and CRC15014 for CB), Agence Nationale de la Recherche (NONAGES, ANR-14-CE15-0012-01 for GJ), Fédération de Cardiologie (for GJ), Société Française de Cardiologie (for GJ), Centre National de Génotypage (JFD), Fondation pour la Recherche en Cardiologie.


MA was supported by an INSERM Poste d’accueil grant. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We are indebted to the clinicians of the National diagnostic network for the Marfan syndrome and related disorders, patients and families. We thank Elisabeth Tournier-Lasserve and Laurence Olivier-Faivre for their expert advice on rare variants in the COL4A1 and SKI genes, respectively.

Authors contributions

Patient recruitment, characterization and data generation: MA, PA, NH, OM, CS, LG, GJ, CB. Genomics and CNV data generation: MA, SG, JB, AB, VM, JFD. Targeted sequencing, Expression studies: MA, PA, LB, MSG, MPJ. Statistical analysis: MA, SG, EG. Steering and manuscript writing committee: MA, SG, PA, LB, MSG, NH, OM, CS, TB, ID, MPJ, LG, EG, JFD, GJ, CB.

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Correspondence to Catherine Boileau.

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