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10.3390/genes11050574
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Article

Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability

by
Thomas Grange
1,
Mélodie Aubart
1,2,
Maud Langeois
3,4,
Louise Benarroch
1,
Pauline Arnaud
1,5,6,
Olivier Milleron
7,
Ludivine Eliahou
7,
Marie-Sylvie Gross
1,
Nadine Hanna
5,
Catherine Boileau
1,5,6,
Laurent Gouya
3,8 and
Guillaume Jondeau
1,6,7,*
1
INSERM U1148, 75018 Paris, France
2
Service de Neurologie Pédiatrique, Hôpital Necker-Enfants malades, AP-HP, Université de Paris, Faculté de médecine Paris Centre, 75006 Paris, France
3
Centre national de référence pour le syndrome de Marfan et apparentés, AP-HP, Hôpital Bichat, 75018 Paris, France
4
CHU Toulouse, 31300 Toulouse, France
5
Centre national de référence pour le syndrome de Marfan et apparentés, Département de génétique, AP-HP, Hôpital Bichat, 75018 Paris, France
6
Université de Paris, UFR Médecine Paris Nord, 75010 Paris, France
7
Centre national de référence pour le syndrome de Marfan et apparentés, Service de cardiologie, AP-HP, Hôpital Bichat, 75018 Paris, France
8
INSERM U1159, 75018 Paris
*
Author to whom correspondence should be addressed.
Genes 2020, 11(5), 574; https://doi.org/10.3390/genes11050574
Submission received: 22 April 2020 / Revised: 9 May 2020 / Accepted: 15 May 2020 / Published: 20 May 2020
(This article belongs to the Special Issue Marfan Syndrome and Related Disorders: Genetic Basis, Molecular Mechanisms, and Genotype–Phenotype Correlations)
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Abstract

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with considerable inter- and intra-familial clinical variability. The contribution of inherited modifiers to variability has not been quantified. We analyzed the distribution of 23 clinical features in 1306 well-phenotyped MFS patients carrying FBN1 mutations. We found strong correlations between features within the same system (i.e., ophthalmology vs. skeletal vs. cardiovascular) suggesting common underlying determinants, while features belonging to different systems were largely uncorrelated. We adapted a classical quantitative genetics model to estimate the heritability of each clinical feature from phenotypic correlations between relatives. Most clinical features showed strong familial aggregation and high heritability. We found a significant contribution by the major locus on the phenotypic variance only for ectopia lentis using a new strategy. Finally, we found evidence for the “Carter effect” in the MFS cardiovascular phenotype, which supports a polygenic model for MFS cardiovascular variability and indicates additional risk for children of MFS mothers with an aortic event. Our results demonstrate that an important part of the phenotypic variability in MFS is under the control of inherited modifiers, widely shared between features within the same system, but not among different systems. Further research must be performed to identify genetic modifiers of MFS severity.
Keywords: marfan; heritability; modifiers; fibrillin marfan; heritability; modifiers; fibrillin

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MDPI and ACS Style

Grange, T.; Aubart, M.; Langeois, M.; Benarroch, L.; Arnaud, P.; Milleron, O.; Eliahou, L.; Gross, M.-S.; Hanna, N.; Boileau, C.; et al. Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability. Genes 2020, 11, 574. https://doi.org/10.3390/genes11050574

AMA Style

Grange T, Aubart M, Langeois M, Benarroch L, Arnaud P, Milleron O, Eliahou L, Gross M-S, Hanna N, Boileau C, et al. Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability. Genes. 2020; 11(5):574. https://doi.org/10.3390/genes11050574

Chicago/Turabian Style

Grange, Thomas, Mélodie Aubart, Maud Langeois, Louise Benarroch, Pauline Arnaud, Olivier Milleron, Ludivine Eliahou, Marie-Sylvie Gross, Nadine Hanna, Catherine Boileau, and et al. 2020. "Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability" Genes 11, no. 5: 574. https://doi.org/10.3390/genes11050574

APA Style

Grange, T., Aubart, M., Langeois, M., Benarroch, L., Arnaud, P., Milleron, O., Eliahou, L., Gross, M.-S., Hanna, N., Boileau, C., Gouya, L., & Jondeau, G. (2020). Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability. Genes, 11(5), 574. https://doi.org/10.3390/genes11050574

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