ArticleEuropean journal of human genetics : EJHG2018
Association of modifiers and other genetic factors explain Marfan syndrome clinical variability.
Article in European journal of human genetics : EJHG, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 1 of them a synthesis that pooled it.
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Who cites it
54 citing papers in PubMed, 1 synthesis or guideline pooled it, 92 citations in OpenAlex.
- Pooled it
- Charting the Phenotypic Landscape of FBN1 Variants in Marfan Syndrome With Ectopia Lentis Through Extreme Phenotype Sampling.Investigative ophthalmology & visual science · 2026Article
- Preclinical modeling of Loeys-Dietz syndrome: insights into mechanisms and therapy.Orphanet journal of rare diseases · 2026Review
- Phenotypic Associations of Early Cardiovascular Surgery in Pediatric Marfan Syndrome.Children (Basel, Switzerland) · 2026Article
- Article
- Genotype-Phenotype Correlations, Treatment, and Prognosis of Children With Early-Onset (Neonatal) Marfan Syndrome.Clinical genetics · 2025Article
- Genome-First Approach to Rare and Common Variant Risk of Thoracic Aortic Aneurysm and Dissection.medRxiv : the preprint server for health sciences · 2025Article
- Spontaneous Coronary Artery Dissection and a Family History of Aortic Dissection: A Genetic Association Study.Journal of the American Heart Association · 2025Article
- Unraveling a novel FBN1 variant in Marfan syndrome with dilated aortic root manifestation.BMC medical genomics · 2025Article
- Clinical Approach to Genetic Cerebral Arteriopathy in the Adult Patient With Ischemic Stroke.Neurology. Genetics · 2024Review
- Functional analysis of cell lines derived from SMAD3-related Loeys-Dietz syndrome patients provides insights into genotype-phenotype relation.Human molecular genetics · 2024Article
- Integrated DNA methylation analysis reveals a potential role for PTPRN2 in Marfan syndrome scoliosis.JOR spine · 2024Article
- TheFrontiers in cardiovascular medicine · 2024Article
- Understanding genomic medicine for thoracic aortic disease through the lens of induced pluripotent stem cells.Frontiers in cardiovascular medicine · 2024Review
- The Antioxidant/Nitric Oxide-Quenching Agent Cobinamide Prevents Aortic Disease in a Mouse Model of Marfan Syndrome.JACC. Basic to translational science · 2024Article
- Integrating oculomics with genomics reveals imaging biomarkers for preventive and personalized prediction of arterial aneurysms.The EPMA journal · 2023Article
- Case Report: Decrypting an interchromosomal insertion associated with Marfan's syndrome: how optical genome mapping emphasizes the morbid burden of copy-neutral variants.Frontiers in genetics · 2023Article
- Review
- Clinical genetics evaluation and testing of connective tissue disorders: a cross-sectional study.BMC medical genomics · 2022Article
- The fibrillinopathies: New insights with focus on the paradigm of opposing phenotypes for both FBN1 and FBN2.Human mutation · 2022Review
Corrections and comments
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Authors and funding
20 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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