Two Novel FBN2 Variants Causing Congenital Contractural Arachnodactyly

Abstract

Congenital contractural arachnodactyly (CCA) is a rare, autosomal dominant connective tissue disease characterized by arachnodactyly, camptodactyly, multiple joint contractures, tall and slender habitus, crumpled ears, and scoliosis. It shares overlapping features with Marfan syndrome (MFS). This condition is caused by pathogenic variants in the fibrillin 2 (FBN2) gene. Currently, approximately 200 variants in FBN2 have been identified, with most of the variants located in the middle region of the gene (Exons 24-35). Here, we investigated the genetic etiology of CCA in two unrelated Chinese families. Whole-exome sequencing (WES) identified a novel in-frame deletion variant, NM_001999.4: c.4195_4209del, p.Trp1399_Gly1403del, in Exon 32 of FBN2 that was detected in all 3 affected patients but absent in 6 unaffected family members. The other novel missense variant in Exon 27 of FBN2 (c.3521G > A, p.Cys1174Tyr) was identified in an 8-month-old female patient who was diagnosed with CCA. This variant was verified to be inherited from her unaffected mother with low-level mosaicism. Our study expands the mutation spectrum of FBN2 and provides insights into the genotype-phenotype relationship in CCA as well as a foundation for its genetic diagnosis, counseling, and management.

Keywords: FBN2; congenital contractural arachnodactyly; connective tissue; genetic counseling; novel variants.