Molecular characterization and investigation of the role of genetic variation in phenotypic variability and response to treatment in a large pediatric Marfan syndrome cohort

Genet Med. 2022 May;24(5):1045-1053. doi: 10.1016/j.gim.2021.12.015. Epub 2022 Jan 17.


Purpose: In a large cohort of 373 pediatric patients with Marfan syndrome (MFS) with a severe cardiovascular phenotype, we explored the proportion of patients with MFS with a pathogenic FBN1 variant and analyzed whether the type/location of FBN1 variants was associated with specific clinical characteristics and response to treatment. Patients were recruited on the basis of the following criteria: aortic root z-score > 3, age 6 months to 25 years, no prior or planned surgery, and aortic root diameter < 5 cm.

Methods: Targeted resequencing and deletion/duplication testing of FBN1 and related genes were performed.

Results: We identified (likely) pathogenic FBN1 variants in 91% of patients. Ectopia lentis was more frequent in patients with dominant-negative (DN) variants (61%) than in those with haploinsufficient variants (27%). For DN FBN1 variants, the prevalence of ectopia lentis was highest in the N-terminal region (84%) and lowest in the C-terminal region (17%). The association with a more severe cardiovascular phenotype was not restricted to DN variants in the neonatal FBN1 region (exon 25-33) but was also seen in the variants in exons 26 to 49. No difference in the therapeutic response was detected between genotypes.

Conclusion: Important novel genotype-phenotype associations involving both cardiovascular and extra-cardiovascular manifestations were identified, and existing ones were confirmed. These findings have implications for prognostic counseling of families with MFS.

Keywords: Clinical genetics; Connective tissue disease; FBN1; Genotype–phenotype associations; Marfan syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Variation, Population
  • Child
  • Ectopia Lentis* / complications
  • Ectopia Lentis* / genetics
  • Fibrillin-1 / genetics
  • Fibrillins / genetics
  • Genotype
  • Humans
  • Marfan Syndrome* / genetics
  • Mutation
  • Phenotype


  • Fibrillin-1
  • Fibrillins