Functional analysis of a novel FBN1 deep intronic variant causing Marfan syndrome in a Chinese patient

Marfan syndrome (MFS MIM#154700), due to pathogenic variants in the <i>FBN1</i> gene, is an autosomal dominant connective tissue disorder, typically involving the skeletal, cardiovascular and ocular systems. Currently, over 3000 MFS patients were reported, and approximately 1800 pathogenic variants in <i>FBN1</i> were identified. However, the molecular diagnosis still remains challenging for 8%-10% of patients with clinical features suggestive of MFS. In this study, we reported a 2-month-old Chinese female patient whose clinical features were compatible with the MFS. Whole-exome sequencing (WES) identified a novel <i>de novo</i> deep intronic variant, c.4943-8_4943-7insTATGTGATATTCAT TCAC in intron 40 of <i>FBN1</i> that was predicted to affect the RNA splicing. Minigene analysis showed that this variant causes skipping of exon 41, leading to the deletion of 41 amino acids (c.4943_5065del, p.Val1649_Asp1689del). It confirmed the pathogenic nature of the variant and established the genotype-phenotype relationship. Our study expands the mutation spectrum of <i>FBN1</i> and emphasizes the importance of deep intronic variant interpretation and the need for additional functional studies to verify the pathogenicity of these variants.