Congenital Contractural Arachnodactyly (Beals Syndrome) via the FBN2 Gene

Congenital Contractural Arachnodactyly (CCA), also known as Beals syndrome, is characterized by a tall, slender habitus in which arm span exceeds height, and arachnodactyly (Hecht and Beals. 1972. PubMed ID: 4552107; Putnam et al. 1995. PubMed ID: 7493032; Wang et al. 1996. PubMed ID: 8900230). Classical CCA patients are diagnosed by a constellation of clinical findings that include the Marfanoid habitus such as flexion contractures of multiple joints including elbows, knees, ankles, hips, fingers and toes; kyphosis/scoliosis, muscular hypoplasia and abnormal pinnae (Wang et al. 1996. PubMed ID: 8900230; Snape et al. 2006. PubMed ID: 16531736; Callewaert et al. 2009. PubMed ID: 19006240; Buchan et al. 2014. PubMed ID: 24833718; Godfrey. 2012. PubMed ID: 20301560). Infants with severe/lethal CCA have cardiovascular and gastrointestinal anomalies. Cardiovascular anomalies include atrial or ventricular septal defect, interrupted aortic arch, single umbilical artery, and rarely aortic root dilatation. Gastrointestinal anomalies include duodenal or esophageal atresia and intestinal malrotation (Wang et al. 1996. PubMed ID: 8900230; Snape et al. 2006. PubMed ID: 16531736).

CCA is inherited in an autosomal dominant manner due to pathogenic variants in in the FBN2 (Putnam et al. 1995. PubMed ID: 7493032; Wang et al. 1996. PubMed ID: 8900230; Callewaert et al. 2009. PubMed ID: 19006240). Many individuals with CCA have an affected parent, but de novo variants have been reported (Callewaert et al. 2009. PubMed ID: 19006240). FBN2 encodes the Fibrillin-2 protein, an extracellular matrix protein that has a calcium-binding EGF-like motif and a TGF binding protein-like motif (Putnam et al. 1995. PubMed ID: 7493032; Wang et al. 1996. PubMed ID: 8900230). A mix of nonsense, splicing, deletion, insertion, duplication and missense pathogenic variants have been reported in the FBN2 gene (Putnam et al. 1995. PubMed ID: 7493032; Wang et al. 1996. PubMed ID: 8900230; Callewaert et al. 2009. PubMed ID: 19006240; Park et al. 1998. PubMed ID: 9714438; Gupta et al. 2002. PubMed ID: 11754102). The majority of CCA pathogenic variants in FBN2 substitute a cysteine residue to another amino acid and reside in the 13th to 23rd calcium binding-epidermal growth factor (cbEGF) like domains (Callewaert et al. 2009. PubMed ID: 19006240). Somatic mosaicism for an FBN2 pathogenic variant has been reported in one case (Putnam et al. 1997. PubMed ID: 9106527).

FBN2 pathogenic variants have been identified in up to 75% of individuals diagnosed with Congenital Contractural Arachnodactyly (Gupta et al. 2002. PubMed ID: 11754102; Callewaert et al. 2009. PubMed ID: 19006240).

This test provides full coverage of all coding exons of the FBN2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.