Case report: Identification of novel fibrillin-2 variants impacting disulfide bond and causing congenital contractural arachnodactyly

Background: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder with clinical features of arthrogryposis, arachnodactyly, crumpled ears, scoliosis, and muscular hypoplasia. The heterozygous pathogenic variants in FBN2 have been shown to cause CCA. Fibrillin-2 is related to the elasticity of the tissue and has been demonstrated to play an important role in the constitution of extracellular microfibrils in elastic fibers, providing strength and flexibility to the connective tissue that sustains the body’s joints and organs. Methods: We recruited two Chinese families with arachnodactyly and bilateral arthrogryposis of the fingers. Whole-exome sequencing (WES) and co-segregation analysis were employed to identify their genetic etiologies. Three-dimensional protein models were used to analyze the pathogenic mechanism of the identified variants. Results: We have reported two CCA families and identified two novel missense variants in FBN2 (NM_001999.3: c.4093T>C, p.C1365R and c.2384G>T, p.C795F). The structural models of the mutant FBN2 protein in rats exhibited that both the variants could break disulfide bonds. Conclusion: We detected two FBN2 variants in two families with CCA. Our description expands the genetic profile of CCA and emphasizes the pathogenicity of disulfide bond disruption in FBN2.

[1]  Zhihong Wu,et al.  Identification of Novel FBN2 Variants in a Cohort of Congenital Contractural Arachnodactyly , 2022, Frontiers in Genetics.

[2]  Hongwei Jiang,et al.  Clinical Characteristics and Genetic Analysis of a Family With Birt-Hogg-Dubé Syndrome and Congenital Contractural Arachnodactyly , 2022, Frontiers in Genetics.

[3]  Dingding Zhang,et al.  The Molecular Genetics of Marfan Syndrome , 2021, International journal of medical sciences.

[4]  W. Chung,et al.  ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG) , 2021, Genetics in Medicine.

[5]  K. Kutsche,et al.  Severe congenital contractural arachnodactyly caused by biallelic pathogenic variants in FBN2. , 2021, European journal of medical genetics.

[6]  G. Mortier,et al.  Delineation of a new fibrillin-2-opathy with evidence for a role of FBN2 in the pathogenesis of carpal tunnel syndrome , 2020, Journal of Medical Genetics.

[7]  Xuan Gao,et al.  A Novel Splicing Mutation in the FBN2 Gene in a Family With Congenital Contractural Arachnodactyly , 2020, Frontiers in Genetics.

[8]  A. Najafi,et al.  Variant filtering, digenic variants, and other challenges in clinical sequencing: a lesson from fibrillinopathies , 2019, Clinical genetics.

[9]  D. Stainier,et al.  Fibrillin-2 is a key mediator of smooth muscle extracellular matrix homeostasis during mouse tracheal tubulogenesis , 2018, European Respiratory Journal.

[10]  A. Gelot,et al.  Mosaic intragenic deletion of FBN2 and severe congenital contractural arachnodactyly , 2017, Clinical genetics.

[11]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[12]  Wei Liu,et al.  A novel FBN2 mutation in a Chinese family with congenital contractural arachnodactyly , 2015, FEBS open bio.

[13]  Mohamed Abouelhoda,et al.  Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. , 2015, Cell reports.

[14]  Ivana K. Kim,et al.  Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration. , 2014, Human molecular genetics.

[15]  K. Devriendt,et al.  A syndromic form of Pierre Robin sequence is caused by 5q23 deletions encompassing FBN2 and PHAX. , 2014, European journal of medical genetics.

[16]  Carlos Cruchaga,et al.  Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis. , 2014, Human molecular genetics.

[17]  R. Mecham,et al.  Ocular phenotype of Fbn2-null mice. , 2013, Investigative ophthalmology & visual science.

[18]  M. Davis,et al.  Structure and function of the mammalian fibrillin gene family: implications for human connective tissue diseases. , 2012, Molecular genetics and metabolism.

[19]  O. Gabrielli,et al.  Comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: Report of 14 novel mutations and review of the literature , 2009, Human mutation.

[20]  D. Milewicz,et al.  The FBN2 gene: new mutations, locus‐specific database (Universal Mutation Database FBN2), and genotype‐phenotype correlations , 2009, Human mutation.

[21]  Y. Alanay,et al.  Orphanet Journal of Rare Diseases BioMed Central Review Congenital contractural arachnodactyly (Beals syndrome) , 2006 .

[22]  I. Kaitila,et al.  Ten novel FBN2 mutations in congenital contractural arachnodactyly: Delineation of the molecular pathogenesis and clinical phenotype , 2002, Human mutation.

[23]  M. W. Bean.  Congenital contractural arachnodactyly. , 1979, American journal of diseases of children.

[24]  F. Hecht,et al.  Congenital contractural arachnodactyly. A heritable disorder of connective tissue. , 1971, The Journal of bone and joint surgery. American volume.