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Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability

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...

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Autores principales: Grange, Thomas, Aubart, Mélodie, Langeois, Maud, Benarroch, Louise, Arnaud, Pauline, Milleron, Olivier, Eliahou, Ludivine, Gross, Marie-Sylvie, Hanna, Nadine, Boileau, Catherine, Gouya, Laurent, Jondeau, Guillaume
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288268/
https://www.ncbi.nlm.nih.gov/pubmed/32443863
http://dx.doi.org/10.3390/genes11050574
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author Grange, Thomas
Aubart, Mélodie
Langeois, Maud
Benarroch, Louise
Arnaud, Pauline
Milleron, Olivier
Eliahou, Ludivine
Gross, Marie-Sylvie
Hanna, Nadine
Boileau, Catherine
Gouya, Laurent
Jondeau, Guillaume
author_facet Grange, Thomas
Aubart, Mélodie
Langeois, Maud
Benarroch, Louise
Arnaud, Pauline
Milleron, Olivier
Eliahou, Ludivine
Gross, Marie-Sylvie
Hanna, Nadine
Boileau, Catherine
Gouya, Laurent
Jondeau, Guillaume
author_sort Grange, Thomas
collection PubMed
description 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.
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spelling pubmed-72882682020-06-17 Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability Grange, Thomas Aubart, Mélodie Langeois, Maud Benarroch, Louise Arnaud, Pauline Milleron, Olivier Eliahou, Ludivine Gross, Marie-Sylvie Hanna, Nadine Boileau, Catherine Gouya, Laurent Jondeau, Guillaume Genes (Basel) Article 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. MDPI 2020-05-20 /pmc/articles/PMC7288268/ /pubmed/32443863 http://dx.doi.org/10.3390/genes11050574 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Grange, Thomas
Aubart, Mélodie
Langeois, Maud
Benarroch, Louise
Arnaud, Pauline
Milleron, Olivier
Eliahou, Ludivine
Gross, Marie-Sylvie
Hanna, Nadine
Boileau, Catherine
Gouya, Laurent
Jondeau, Guillaume
Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability
title Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability
title_full Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability
title_fullStr Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability
title_full_unstemmed Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability
title_short Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability
title_sort quantifying the genetic basis of marfan syndrome clinical variability
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288268/
https://www.ncbi.nlm.nih.gov/pubmed/32443863
http://dx.doi.org/10.3390/genes11050574
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