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

Josephina A.N. Meester, Silke Peeters, Lotte Van Den Heuvel, Geert Vandeweyer, Erik Fransen, Elizabeth Cappella, Harry C. Dietz, Geoffrey Forbus, Bruce D. Gelb, Elizabeth Goldmuntz, Arvind Hoskoppal, Andrew P. Landstrom, Teresa Lee, Seema Mital, Shaine Morris, Aaron K. Olson, Marjolijn Renard, Dan M. Roden, Michael N. Singh, Elif Seda Selamet TierneyJustin T. Tretter, Sara L. Van Driest, Marcia Willing, Aline Verstraeten, Lut Van Laer, Ronald V. Lacro, Bart L. Loeys

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1045-1053
Number of pages9
JournalGenetics in Medicine
Volume24
Issue number5
DOIs
StatePublished - May 2022

Keywords

  • Clinical genetics
  • Connective tissue disease
  • FBN1
  • Genotype–phenotype associations
  • Marfan syndrome

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