Case Report: A novel variant in fibrillin-2 identified in a congenital contractural arachnodactyly family with phenotypic heterogeneity.

BACKGROUND AND OBJECTIVES: Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant connective tissue disorder, and FBN2 is its only known causative gene. CCA is characterized by joint contractures, arachnodactyly, scoliosis, and crumpled ears. Due to its rarity, phenotypic diversity, heterogeneity, and clinical overlap with conditions such as Marfan syndrome (MFS), the diagnosis remains challenging, and genetic screening plays a critical role in facilitating accurate diagnosis. We recruited a CCA family with three patients across three generations and detected their genetic etiology.

CASE PRESENTATION: The proband exhibited the Marfanoid habitus with a height of 121 cm (> + 3 SD), a weight of 16 kg (-2 SD ∼-1 SD), arachnodactyly, and long bone overgrowth. He had joint contractures in the 2nd ∼ 5th fingers of bilateral hands and 2nd and 5th toes of the left foot. His mother and grandmother also presented arachnodactyly and arachnodactyly. They were confirmed to be affected with CCA.

RESULTS: A novel heterozygous missense variant in the exon 30 of FBN2 (NM_001999.4: c.3916T > G, p.Y1306D) was identified by whole-exome sequencing. The variant was classified as "likely pathogenic" according to the American College of Medical Genetics and Genomics guidelines and standards. Bioinformatics predictions revealed that the variant altered the hydrophobicity, extended an intrinsically disordered protein region, disrupted a benzene ring structure on a β-sheet, and modified the surface charge of the fibrillin-2 partial region.

CONCLUSION: We descripted a CCA family and identified a novel FBN2 variant. Our findings extended the variant spectrum of FBN2, contributing to the genetic counseling and molecular diagnostics for CCA.