Skeletal dysplasia

Gene: FBN2

Red List (low evidence)

Comment on list classification: Heterozygous variants in FBN2 are known to cause congenital contractural arachnodactyly. These patients do not tend to have skeletal defects beyond mild digit anomalies (camptodactyly, arachnodactyly). Tall stature was found to be associated with FBN1, but I did not find evidence of association with FBN2 variants. There are also 4 cases reported with biallelic FBN2 variants and various presentations, none with skeletal manifestations beyond digit anomalies. Hence, this gene should be downgraded to Red on the Skeletal dysplasia panel. An expert-review tag was added as this is a proposed demotion from Green rating.

Created: 6 Aug 2026, 4:32 p.m. | Last Modified: 6 Aug 2026, 4:39 p.m.

Panel Version: 9.33

MONOALLELIC CASES:
PMID: 35360850 Sun et al., 2022
Report of 27 congenital contractural arachnodactyly (CCA) patients from 10 families, harbouring heterozygous FBN2 variants (mostly missense, 2 confirmed de novo).
Arachnodactyly (27/27, 100%), crumpled ears (26/27, 96.3%), camptodactyly (26/27, 96.3%), and muscle hypoplasia (22/26, 85%) were observed in almost all recruited cases. More than half patients (16/25, 64%) presented with contracture of large joints, including elbow, wrist, knee, ankle, and shoulder. 54% patients (13/24) present with kyphosis or scoliosis; 29% patients (7/24) presented with pectus deformity, including four patients with pectus carinatum and three patients with pectus excavatum; 74% patients (17/23) presented with high arched palate and 71% patients (17/24) presented with micrognathia; 33% patients (9/27) presented with pes planus.
No wider skeletal defects noted beyond mild digit anomalies. No patient presented with dolichostenomelia (disproportionately long limbs).

PMID: 24833718 Buchan et al., 2014
Study of 852 adolescent idiopathic scoliosis cases and 669 controls.
In individuals of European ancestry, rare variants in FBN1 and FBN2 were enriched in severely affected AIS cases (7.6%) compared with in-house controls (2.4%) (OR = 3.5, P = 5.46 × 10(-4)) and Exome Sequencing Project controls (2.3%) (OR = 3.5, P = 1.48 × 10(-6))
FBN1 variants associated with tall stature - not noted in FBN2.

Created: 6 Aug 2026, 4:26 p.m. | Last Modified: 6 Aug 2026, 4:26 p.m.

Panel Version: 9.33

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: 9.33

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

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

Publications

• 24833718
• 25558065
• 28383543
• 33571691
• 35360850
• 38791509

Green List (high evidence)

Overgrowth (tall stature) syndromes with skeletal involvement gp of SD - at least 3 cases reported. Variants also associated with early-onset macular degeneration - 616118.; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Contractural arachnodactyly, congenital 121050

I don't know

The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 6 Mar 2022, 6:30 p.m. | Last Modified: 6 Mar 2022, 6:30 p.m.

Panel Version: 2.184

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: FBN2; Initial rating suggestion: green

Created: 6 Mar 2019, 11:36 a.m.

It would appear from PMIDs 33571691, 25558065 & 28383543 that biallelic variants should be considered for this gene and as such the MOI should be changed to BOTH monallelic and biallelic, autosomal or pseudoautosomal.

Created: 28 Apr 2021, 12:31 p.m. | Last Modified: 28 Apr 2021, 12:31 p.m.

Panel Version: 2.91

Comment when marking as ready: Associated with phenotypes in OMIM and with contractural arachnodactyly, congenital 121050 in G2P. Numerous variants reported contractural arachnodactyly, congenital 121050 and at least two in Macular degeneration, early-onset 616118

Created: 28 Jul 2016, 11:33 a.m.

Comment on phenotypes: Variants also reported in Macular degeneration, early-onset 616118

Created: 28 Jul 2016, 11:31 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Green List (high evidence)

Tier 1

Created: 17 Jun 2016, 8:03 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

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

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