Ehlers Danlos syndrome with a likely monogenic cause

Gene: FBN1

Green List (high evidence)

Comment on mode of inheritance: There are numerous individuals with Marfan syndrome reported with both heterozygous and biallelic FBN1 variants - though biallelic cases are known to present with more severe features, and with higher disease penetrance. Hence, the MOI on Ehlers Danlos syndrome with a likely monogenic cause should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.

Created: 22 May 2026, 2:35 p.m. | Last Modified: 22 May 2026, 2:39 p.m.

Panel Version: 4.11

PMID: 23278365 Hogue et al., 2013
Report of a proband (Mexican-American woman, consanguineous parents) + literature review of 4 additional unrelated families with biallelic FBN1 variants and severe Marfan syndrome - heterozygous parents were either asymptomatic or had a milder form of Marfan syndrome. Mostly biallelic missense, one instance of missense + deletion in 2 sibs. Proband presented with scoliosis, arachnodactyly, dislocated lenses, mitral valve prolapse, aortic dilatation, dural ectasias.

PMID: 27582083 Arnaud et al., 2017
In a large cohort of Marfan syndrome patients, 4 probands were homozygous and 22 potentially comp het for FBN1 variants (5 confirmed to be in trans). All 4 homozygous individuals harboured missense variants; comp het cases either had biallelic missense FBN1 variants, or missense + nonsense. Heterozygous carriers usually also diagnosed with MFS, sometimes very mild e.g., isolated mild skeletal features in women. The severity of symptoms and age of onset varied a lot, both between biallelic and among monoallelic cases.

PMID: 31950671 McInerney-Leo et al., 2020
Report of a pedigree with Marfan syndrome (ectopia lentis, though the skeletal phenotype is variable, and not all have aortic dilatation) - some individuals with monoallelic and some with biallelic FBN1 variants.
All subjects with Marfan syndrome harboured p.Tyr754Cys in FBN1. An additional variant (p.Met2273Thr), previously associated with 'incomplete' MFS, was identified in three siblings. These three compound heterozygous individuals had aortic dilatation at early age (all <30 years): one also had cerebral and ocular aneurysms; and one, who had undergone surgical repair aged 18 years, died from aortic dissection at 31 years.
The heterozygous father (p.Tyr754Cys) with MFS died at 57 years (myocardial infarction) without requiring surgical intervention and one heterozygous (p.Tyr754Cys) sibling has aortic dilatation presenting >40 years but not requiring surgical intervention. Another heterozygous (p.Tyr754Cys) sibling did require aortic root repair (28 years). The heterozygous (p.Met2273Thr) mother had aortic dilatation diagnosed at age 68 years but has not required surgical repair.

The association between FBN1 and Marfan syndrome is rated as Definitive in Gene2Phenotype, both for the AD and AR inheritance patterns.

Created: 22 May 2026, 2:35 p.m. | Last Modified: 22 May 2026, 2:35 p.m.

Panel Version: 4.9

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Marfan syndrome, OMIM:154700; Marfan syndrome, MONDO:0007947

Publications

• 23278365
• 27582083
• 31950671

Green List (high evidence)

I don't know

This gene was part of an initial gene list collated by Duncan Baker, Sheffield Diagnostic Genetics Service, January 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: FBN1; Suggested initial gene rating: green

Created: 3 Apr 2019, 3:41 p.m.

Green List (high evidence)

Green List (high evidence)

I don't know

Refer to clinical team for further discussion on wether we should include FBN1on the EDS panel. There is clinical overlap between EDS and other Heritable Connective Tissue Disorders.

Created: 7 Apr 2017, 3:25 p.m.

Comment on list classification: Marfan syndrome is an important differential we should not miss in this group.

Created: 11 May 2016, 12:50 p.m.