Arthrogryposis

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 be changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown.

Created: 6 Aug 2026, 3:56 p.m. | Last Modified: 6 Aug 2026, 3:56 p.m.

Panel Version: 10.15

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: 10.15

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)

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

Created: 11 Mar 2022, 1:41 p.m. | Last Modified: 11 Mar 2022, 1:41 p.m.

Panel Version: 3.154

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, 12:11 p.m. | Last Modified: 28 Apr 2021, 12:11 p.m.

Panel Version: 3.95

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Green List (high evidence)

Association between mono-allelic variants and CCA is well established.

Kloth (2021): report biallelic FBN2 variants (PTC/missense) in a teenager with severe CCA, including cardiac defects, mild scoliosis and muscular involvement. Carrier parents both "healthy/unaffected". Phenotype matches mouse K/O.
Authors performed a literature review and identified an additional 2 homozygous patients (both missense variants) with
- fetal akinesia, brain ischemia and neonatal death
- severe muscle weakness with bilateral clubfeet, a pronounced gait disturbance, recurrent patellar dislocations, flexion contractures, camptodactyly, widespread striae and an unusual myofibrillar disorganization, variation in fiber size and atrophic fibers in muscle biopsy

Created: 17 Apr 2021, 7:50 a.m. | Last Modified: 17 Apr 2021, 7:50 a.m.

Panel Version: 3.91

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

Phenotypes
Contractural arachnodactyly, congenital MIM#121050

Publications

• 33571691

Green List (high evidence)

Comment on mode of pathogenicity: Dominant negative mutations

Created: 4 Jan 2017, 4:17 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Contractural arachnodactyly, congenital 121050

Publications

• 7493032

Mode of pathogenicity
Other