Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Sep 9:41:101140.
doi: 10.1016/j.ymgmr.2024.101140. eCollection 2024 Dec.

Missense variants of FBN2 associated with congenital arachnodactyly in three Chinese families

Yu Sui  1 , Yongping Lu  1 , Meina Lin  1 , Xinren Chen  1 , Xiang Ni  1 , Huan Li  1 , Miao Jiang  1
Affiliations

Missense variants of FBN2 associated with congenital arachnodactyly in three Chinese families

Yu Sui et al. Mol Genet Metab Rep. .

Abstract

Background: Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant disorder caused by pathogenic variants of Fibrillin-2 (FBN2) gene. This study aimed to investigate the variants in three Chinese families with CCA.

Methods: Next-generation sequencing analysis and Sanger sequencing of exons 24-35 of FBN2 (NM_001999.4) were performed on the three CCA pedigrees. The pathogenicity of the variants was assessed using ACMG criteria and predicted using an in-silico program.

Results: A novel heterozygous substitution (NM_001999.4: c.3230G > A; NP_001990.2 p. Cys1077Tyr) was identified in all patients from pedigree A, but not in healthy family members. The variant was found to be pathogenic. Additionally, in pedigree B (NM_001999.4: c.4222G > A; NP_001990.2: p.Asp1408Asn) and C (NM_001999.4: c.3170G > A; NP_001990.2: p.Gly1057Asp), and the previously reported variants were detected. Variants affecting cysteine residues may disrupt disulfide bridging, leading to a weakened microfibril scaffold, resulting in CCA phenotypes. High phenotypic heterogeneity was observed among different families, and there was little correlation between the genotype and phenotype.

Conclusion: This study describes three large families with CCA caused by missense variants in the FBN2 gene. Phenotypic variations were observed among different pedigree groups, and further research is needed to investigate the underlying reasons for these variations.

Keywords: Congenital contractural arachnodactyly (CCA); FBN2; Heterogeneity.

PubMed Disclaimer

Conflict of interest statement

The authors declare that there is no competing interest in this research.

Figures

Unlabelled Image
Graphical abstract
Fig. 1
Fig. 1
Pedigree of 3 CCA families. Fig. 1-1 Pedigree A. Fig. 1-2 Pedigree B. Fig. 1-3 Pedigree C. Black symbol represents affected individuals, and an arrow indicates the proband.
Fig. 2
Fig. 2
Sanger sequencing results of 3 CCA pedigrees. Fig. 2–1 Sanger sequencing result showing a heterozygous change c.3230G > A in FBN2. Fig. 2–2 Sanger sequencing result showing a heterozygous change c.4222G > A in FBN2. Fig. 2–3 Sanger sequencing result showing a heterozygous changec.3170G > A in FBN2. Sanger sequence analyses of affected individuals and normal unaffected controls. The mutant and wild-type variants are indicated by black arrows.
Fig. 3
Fig. 3
Phenotypes of proband in pedigree A. Fig. 3–1 Full length portrait of the proband in pedigree A. Fig. 3–2 Left side profile of the proband in pedigree A. Fig. 3–3 Right side profile of the proband in pedigree A. Fig. 3–4 Dorsum manus of the proband in pedigree A. Fig. 3–5 Palm of the proband in pedigree A.
Fig. 4
Fig. 4
Phenotypes of proband in pedigree B. Fig. 4–1 Frontal image of the patient of proband in pedigree B. Fig. 4–2 Dorsum manus of the proband in pedigree B. Fig. 4–3 Palm of the proband in pedigree B. Fig. 4–4 Foot of the proband in pedigree B.
Fig. 5
Fig. 5
Phenotypes of proband in pedigree C. Fig. 5–1,2 Slender, contractual clubbed fingers. Fig. 5–3 Slender, contractual clubbed toes. Fig. 5–4 Crumpled ears presented among all patients. Fig. 5–5 Scoliosis and the resultant depressed of the spine.
Fig. 6
Fig. 6
The intact and broken disulfide bond in wild type and variant type. Fig. 6 The intact and broken disulfide bonds are indicated by black arrows.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Gupta P.A., et al. Ten novel FBN2 mutations in congenital contractural arachnodactyly: delineation of the molecular pathogenesis and clinical phenotype. Hum. Mutat. 2002;19(1):39–48. - PubMed
    1. Lee B., et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature. 1991;352(6333):330–334. - PubMed
    1. Dietz H.C., et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352(6333):337–339. - PubMed
    1. Tsipouras P., et al. Genetic linkage of the Marfan syndrome, ectopia lentis, and congenital contractural arachnodactyly to the fibrillin genes on chromosomes 15 and 5. The international Marfan syndrome collaborative study. N. Engl. J. Med. 1992;326(14):905–909. - PubMed
    1. Putnam E.A., et al. Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly. Nat. Genet. 1995;11(4):456–458. - PubMed

LinkOut - more resources