Ehlers Danlos syndrome with a likely monogenic cause

Gene: FBN2

Green List (high evidence)

Comment on mode of inheritance: There are 4 unrelated individuals reported in literature with biallelic FBN2 variants. However, these individuals presented with a spectrum of phenotypes: one with dextro-transposition of the great arteries, one with congenital contractural arachnodactyly, one individual with a myofibrillar myopathy, and one fetal case with fetal akinesia with brain ischemia and neonatal death. Hence, the mode of inheritance should remain MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown, until more evidence emerges.

Created: 6 Aug 2026, 3:53 p.m. | Last Modified: 6 Aug 2026, 3:53 p.m.

Panel Version: 4.16

BIALLELIC CASES:
PMID: 38791509 Zodanu et al., 2024
Proband B was prenatally diagnosed with dextro-transposition of the great arteries, based on a fetal echocardiogram at 20 weeks of gestation and required cardiac surgery at 0 and 5 days after birth. WES of proband B and his parents, showed compound heterozygous missense, c.518C>T and c.8230T>G (p.Tyr2744Asp), variants in the FBN2 in proband B; unaffected parents confirmed het for one variant each.

PMID: 33571691 Kloth et al., 2021
Report of a 15-year-old girl with a severe form of congenital contractural arachnodactyly and novel biallelic variants in FBN2: the missense variant c.3563G > T/p.(Gly1188Val) from her unaffected father and the nonsense variant c.6831C > A/p.(Cys2277*) from her healthy mother.

PMID: 28383543 Monies et al., 2017
Family 16DG0107 - male proband homozygous for FBN2 variant NM_001999.3:c.41T>G:p.(Leu14Arg) - het in unaffected parents and sibs. Variant not found in gnomAD v4. Proband presented at birth with clubfoot. At 13 yrs he had fatigue, mild to severe muscle weakness (severe in hip extensors), camptodactyly. The CK value was normal, but muscle biopsy showed myofibrillar disorganization.

PMID: 25558065 Alazami et al., 2015
Large cohort of consanguineous families. Method: WES.
Individual 12DG0104 had a FBN2 variant NM_001999:c.1064G>A, p.G355D, and presented with fetal akinesia with brain ischemia and neonatal death.

FBN2 is associated with AD Contractural arachnodactyly, congenital, OMIM:121050 in OMIM. The association between FBN2 and AD congenital contractural arachnodactyly is classified as Definitive in ClinGen (Nov 2025, Hereditary Cardiovascular Disease GCEP). Resources accessed 6th Aug 2026.

Created: 6 Aug 2026, 3:49 p.m. | Last Modified: 6 Aug 2026, 3:50 p.m.

Panel Version: 4.14

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Contractural arachnodactyly, congenital, OMIM:121050; congenital contractural arachnodactyly, MONDO:0007363

Publications

• 25558065
• 28383543
• 33571691
• 38791509

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: FBN2; 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 this gene on the EDS panel. There is clinical overlap between EDS and other Heritable Connective Tissue Disorders.

Created: 28 Apr 2017, 11:49 a.m.

Comment on phenotypes: There is clinical overlap between EDS and other Heritable Connective Tissue Disorders like Congenital contractural arachnodactyly, which is a rare, autosomal dominant connective tissue disorder characterized by contractures, arachnodactyly, scoliosis, and crumpled ears and specifically shares overlapping features with Marfan syndrome.

Created: 26 Apr 2017, 1:36 p.m.

Comment on publications: Added publications to support gene is involved in the disorder(s) in 3 or more unrelated cases

Created: 26 Apr 2017, 12:42 p.m.