Impact of pathogenic <i>FBN1</i> variant types on the development of severe scoliosis in patients with Marfan syndrome.

Abstract

Among the several musculoskeletal manifestations in patients with Marfan syndrome, spinal deformity causes pain and respiratory impairment and is a great hindrance to patients' daily activities. The present study elucidates the genetic risk factors for the development of severe scoliosis in patients with Marfan syndrome. We retrospectively evaluated 278 patients with pathogenic or likely pathogenic <i>FBN1</i> variants. The patients were divided into those with (n=57) or without (n=221) severe scoliosis. Severe scoliosis was defined as (1) patients undergoing surgery before 50 years of age or (2) patients with a Cobb angle exceeding 50° before 50 years of age. The variants were classified as protein-truncating variants (PTVs), which included variants creating premature termination codons and inframe exon-skipping, or non-PTVs, based on their location and predicted amino acid alterations, and the effect of the <i>FBN1</i> genotype on the development of severe scoliosis was examined. The impact of location of <i>FBN1</i> variants on the development of severe scoliosis was also investigated. Univariate and multivariate analyses revealed that female sex, PTVs of <i>FBN1</i> and variants in the neonatal region (exons 25-33) were all independent significant predictive factors for the development of severe scoliosis. Furthermore, these factors were identified as predictors of progression of existing scoliosis into severe state. We elucidated the genetic risk factors for the development of severe scoliosis in patients with Marfan syndrome. Patients harbouring pathogenic <i>FBN1</i> variants with these genetic risk factors should be monitored carefully for scoliosis progression.