Three FBN1 pathogenic variants in Chinese patients with Marfan syndrome: Two novel variants including a splicing-altering deletion with functional verification.

BACKGROUND: Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder. The clinical manifestations are pleiotropic, predominantly affecting the cardiovascular system (atrioventricular valve prolapse and regurgitation and aortic complications), the skeletal system (disproportionate elongation of long bones), and the ocular system (ectopia lentis and myopia). Pathogenic variants in the fibrillin-1 gene (FBN1) are the primary genetic cause of MFS. METHODS: This study enrolled three Han-Chinese patients from three unrelated families, all of whom underwent comprehensive clinical assessments. Whole exome sequencing was used to screen for candidate variants, which were subsequently confirmed by Sanger sequencing. Further variant analyses, including bioinformatics-based prediction of variant pathogenicity, were then performed. For the potential splicing variant, a minigene construct was designed to evaluate its in vitro splicing effect. RESULTS: Three heterozygous FBN1 variants were respectively identified in three probands, comprising a novel deletion (c.239_247 + 6del), a previously reported nonsense variant (c.4615C > T, p.(Arg1539*)), and a novel missense variant (c.6821G > A, p.(Cys2274Tyr)). Both in silico predictions and the in vitro minigene assay demonstrated the deletion of the terminal 11 nucleotides of exon 3 caused by c.239_247 + 6del variant, which is expected to cause a truncated protein, p.(Gln79Hisfs*46). CONCLUSIONS: In this study, pathogenic FBN1 variants were identified in three patients, thereby confirming the clinical diagnosis of MFS. These findings facilitate diagnostic confirmation and genetic counseling for the affected families, contribute two novel variants to the FBN1 variant repository, and provide a comparative assessment of genotype-phenotype correlations.