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

Publication ,  Journal Article
Meester, JAN; Peeters, S; Van Den Heuvel, L; Vandeweyer, G; Fransen, E; Cappella, E; Dietz, HC; Forbus, G; Gelb, BD; Goldmuntz, E; Hoskoppal, A ...
Published in: Genet Med
May 2022

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.

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Published In

Genet Med

DOI

EISSN

1530-0366

Publication Date

May 2022

Volume

24

Issue

5

Start / End Page

1045 / 1053

Location

United States

Related Subject Headings

  • Phenotype
  • Mutation
  • Marfan Syndrome
  • Humans
  • Genotype
  • Genetics & Heredity
  • Fibrillins
  • Fibrillin-1
  • Ectopia Lentis
  • Child
 

Citation

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Meester, J. A. N., Peeters, S., Van Den Heuvel, L., Vandeweyer, G., Fransen, E., Cappella, E., … Loeys, B. L. (2022). 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, 24(5), 1045–1053. https://doi.org/10.1016/j.gim.2021.12.015
Meester, Josephina A. N., Silke Peeters, Lotte Van Den Heuvel, Geert Vandeweyer, Erik Fransen, Elizabeth Cappella, Harry C. Dietz, et al. “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 24, no. 5 (May 2022): 1045–53. https://doi.org/10.1016/j.gim.2021.12.015.
Meester JAN, Peeters S, Van Den Heuvel L, Vandeweyer G, Fransen E, Cappella E, et al. 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):1045–53.
Meester, Josephina A. N., et al. “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, vol. 24, no. 5, May 2022, pp. 1045–53. Pubmed, doi:10.1016/j.gim.2021.12.015.
Meester JAN, Peeters S, Van Den Heuvel L, Vandeweyer G, Fransen E, Cappella E, Dietz HC, Forbus G, Gelb BD, Goldmuntz E, Hoskoppal A, Landstrom AP, Lee T, Mital S, Morris S, Olson AK, Renard M, Roden DM, Singh MN, Selamet Tierney ES, Tretter JT, Van Driest SL, Willing M, Verstraeten A, Van Laer L, Lacro RV, Loeys BL. 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.

Published In

Genet Med

DOI

EISSN

1530-0366

Publication Date

May 2022

Volume

24

Issue

5

Start / End Page

1045 / 1053

Location

United States

Related Subject Headings

  • Phenotype
  • Mutation
  • Marfan Syndrome
  • Humans
  • Genotype
  • Genetics & Heredity
  • Fibrillins
  • Fibrillin-1
  • Ectopia Lentis
  • Child