Thoracic aortic aneurysm or dissection (GMS)

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, 3:55 p.m. | Last Modified: 6 Aug 2026, 3:55 p.m.

Panel Version: 5.5

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, 3:55 p.m. | Last Modified: 6 Aug 2026, 3:55 p.m.

Panel Version: 5.5

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)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Contractural arachnodactyly, congenital 121050; Macular degeneration, early-onset 616118

Publications

• 25944730
• 29907982

Green List (high evidence)

On CGGL Royal Brompton panel. Phenotypic overlap with MFS, although weaker association with aortic dissection/aneurysm, but some good evidence (PMID: 19006240; 25944730, although FBN2 variants in this paper were VUS). Appropriate for inclusion based on phenotypic overlaps.

Created: 18 Sep 2019, 2:26 p.m. | Last Modified: 18 Sep 2019, 2:26 p.m.

Panel Version: 0.30

Phenotypes
Congenital contractural arachnodactyly

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.

Created: 18 Nov 2019, 4:33 p.m. | Last Modified: 18 Nov 2019, 4:33 p.m.

Panel Version: 0.35

Comment on list classification: Promoted from amber to green based on expert reviews.

Created: 17 Sep 2019, 8:19 a.m. | Last Modified: 17 Sep 2019, 8:19 a.m.

Panel Version: 0.30

Green List (high evidence)

Present on Wessex aortopathy panel.
Associated with congenital contractural arachnodactyly (OMIM #121050), which has significant phenotypic overlap with Marfan syndrome.

Created: 29 Aug 2019, 2:07 p.m. | Last Modified: 29 Aug 2019, 2:07 p.m.

Panel Version: 0.5

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Congenital contractural arachnodactyly

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

121050 Contractural arachnodactyly - CTD including aortic root dilatation, patent ductus arteriosus, BAV, VSD, ASD, mitral valve prolapse and mitral regurgitation

Created: 25 Mar 2019, 4:30 p.m.

Wooderchak-Donahue et al 2015 Am J Med Genet A 167A:1747 PMID:25944730 5 missense variants identified in Marfan/Marfan-like cohort: 3302A>G Asn1101Ser, 3793G>A Glu1265Lys, 4454A>G Asp1485Gly, 4657C>T Arg1553Cys, 5627G>C Cys1876Ser - all reported as VUS. Callewaert et al 2009 Hum Mutat 30:334 PMID:19006240 review FBN2 variants in contractural arachnodactyly and comment on involvement of aortopathy in phenotype of more recently described cases.

Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

I don't know

This gene was part of an initial gene list collated by Matthew Edwards Royal Brompton Hospital sent 16th Jan 2019 on behalf of the London South GLH for review by the GMS Cardiology Specialist Group. Only gene symbol from the Royal Brompton gene panel was provided - suggested initial gene rating and evidence for inclusion not provided with the list.

Created: 20 Feb 2019, 2:17 p.m.

Not on the Inherited Cardiac Condition Genes panel for familial aortic anuerysm, reported in: Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes, Pua et al, Journal of Cardiovascular Translational Research, online Feb 2016 (doi:10.​1007/​s12265-016-9673-5). The panel contains disease-causing, putatively pathogenic, research and phenocopy genes.

Created: 19 Feb 2016, 10:49 a.m.

I don't know

Strong association with contractural arachnodactyly. However, in the context of familial thoracic aortic aneurysm, evidence is much weaker with only a single case report complicated with Aortic Dilatation and Dissection (see PMID above) and other weak association with progressive aortic dilatation (ref within above case report).

Created: 9 Feb 2016, 3:38 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
#121050 - Contractural arachnodactyly, congenital; #616118- Macular degeneration, early-onset

Publications

• PMID: 25975422

I don't know

Reported dilatations are infrequent and relatively mild. No reported dissections associated with FBN2 mutations to date. Although strong evidence for causation of CCA and associated defects, evidence for involvement in FTAAD is less clear.

Created: 13 Nov 2015, 4:31 p.m.