FBN2 pathogenic variants in congenital contractural arachnodactyly with severe cardiovascular manifestations

ABSTRACT

Purpose

Congenital contractural arachnodactyly (CCA) is an extremely rare autosomal dominant connective tissue genetic disorder caused by pathogenic variants in FBN2. CCA is characterized by arachnodactyly, camptodactyly, contracture of major joints, scoliosis, pectus deformities, and crumpled ears, but rarely with lethal cardiovascular manifestations as in Marfan syndrome. It is imperative to conduct a comprehensive analysis and review of the pathogenesis of CCA resulting from pathogenic variants in FBN2 gene.

Materials and Methods

Using whole-exome sequencing and Sanger sequencing, we identified a novel pathogenic splice-altering variant (c.4472-3C>A) in intron 34 of FBN2 gene in a CCA pedigree. The transcriptional result of the splicing-altering variant was analyzed by RNA sequencing. We systematically analyzed the clinical manifestations of all reported cases of CCA caused by splicing-altering pathogenic variants and focused on all the pathogenic variants in FBN2 gene that are associated with severe cardiovascular manifestations.

Results

The splice-altering variant (c.4472-3C>A) in FBN2 was demonstrated to result in the exon 35 skipping and cause an in-frame deletion. Furthermore, we identified exons 31 to 35 may be a hotspot region in FBN2 gene associated with severe cardiovascular phenotype.

Conclusions

This study enriched the pathogenic spectrum of CCA and identified a hotspot region in FBN2 gene associated with severe cardiovascular manifestations. We recommend that patients carrying pathogenic variants in exons 31 to 35 of FBN2 pay more attention to cardiac evaluation.

KEYWORDS:

• Congenital contractural arachnodactyly
• FBN2
• cardiovascular manifestation
• whole exome sequencing
• exon skipping

Acknowledgments

We thank all the participants who provided samples and clinical information for this study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data presented in this study are deposited in the SRA repository (https://dataview.ncbi.nlm.nih.gov/object/SRR22044259), accession number SRR22044259.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/03008207.2024.2340004.

Additional information

Funding

This work was supported by the National Nature Science Foundation of China grants [82370489].