A Novel Mutation of the FBN1 Gene in a Chinese Family With Marfan Syndrome and Unanticipated Discoveries of Family Members

Abstract

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by pathogenic variants in the FBN1 gene. Using whole‐exome sequencing (WES) in a Chinese MFS family, we identified a novel heterozygous nonsense variant FBN1:c.1415dup;p.(Tyr472Ter), which cosegregates with the disease phenotype and results in protein truncation. Immunohistochemical analysis confirmed markedly reduced fibrillin‐1 expression in the aortic wall of variant carriers, and this variant was classified as pathogenic. Unexpectedly, the proband’s younger sister harbors three independent pathogenic variants responsible for MFS, familial hypercholesterolemia (FH), and oculopharyngeal muscular dystrophy (OPMD). Further transcript validation and functional assays demonstrated that the LDLR:c.1987+1G > A;p.Arg662_Gly663insAspLys splice‐site mutation generates a stable in‐frame insertion transcript, impairing protein structure and function. Supported by robust functional evidence and familial cosegregation, this LDLR variant was upgraded from a variant of uncertain significance to pathogenic. We provided formal genetic counseling, long‐term clinical follow‐up, and multidisciplinary surveillance to all affected family members, with particularly comprehensive management for the proband’s sister. This study expands the mutational spectrum of FBN1, establishes functional evidence for the pathogenicity of the LDLR variant, and represents the first report of a pediatric individual carrying three coexisting pathogenic variants for rare diseases. Our findings provide critical insights for molecular diagnosis, genetic counseling, and clinical risk stratification in affected families.