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

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  1 , Silke Peeters  1 , Lotte Van Den Heuvel  1 , Geert Vandeweyer  1 , Erik Fransen  2 , Elizabeth Cappella  3 , Harry C Dietz  4 , Geoffrey Forbus  5 , Bruce D Gelb  6 , Elizabeth Goldmuntz  7 , Arvind Hoskoppal  8 , Andrew P Landstrom  9 , Teresa Lee  10 , Seema Mital  11 , Shaine Morris  12 , Aaron K Olson  13 , Marjolijn Renard  14 , Dan M Roden  15 , Michael N Singh  16 , Elif Seda Selamet Tierney  17 , Justin T Tretter  18 , Sara L Van Driest  15 , Marcia Willing  19 , Aline Verstraeten  1 , Lut Van Laer  1 , Ronald V Lacro  16 , Bart L Loeys  20
Affiliations

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 et al. Genet Med. 2022 May.

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.

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

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Conflict of interest statement

Conflict of Interest The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Patient cohort and workflow of molecular characterization.
Overview of the participants included in this study and the results of their molecular screening. aIdentifiers (IDs) of patients with bad quality DNA: 372 and 373. bIDs of patients who did not have an FBN1 variant described in their patient report and were not sequenced in our genetic ancillary study: 369, 370, and 371. del, deletion; dup, duplication; MLPA, multiplex ligation-dependent probe amplification; NGS, next-generation sequencing; P/LP, pathogenic or likely pathogenic; PHN, Pediatric Heart Network; TAAD, Thoracic Aortic Aneurysm and Dissection; VUS, variant of uncertain significance
Figure 2
Figure 2. Workflow of genotype–phenotype analysis.
Overview ofthe variant workflow, functional classification, and variant types. cys, cysteine; del, deletion; DN, dominant negative; dup, duplication; HI, haploinsufficient; P/LP, pathogenic or likely pathogenic; PHN, Pediatric Heart Network.
Figure 3
Figure 3. Effect of location of DN variants on the proportion of ectopia lentis.
Groups were made on the basis of the proportion of ectopia lentis. DN, dominant negative.
Figure 4
Figure 4. Effect of variant type (DN vs HI) and treatment (atenolol vs losartan) on response to treatment.
Boxplot of the change of aortic root z-score per year for the different groups.The thick line in the middle is the median. The green box shows the first and third quartiles. The whiskers show the maximum and minimum values, with the exceptions of outliers (circles). DN, dominant negative; HI, haploinsufficient.
See this image and copyright information in PMC

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