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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MDPI AG
2020-05-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/11/5/574 |
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| author | Thomas Grange Mélodie Aubart Maud Langeois Louise Benarroch Pauline Arnaud Olivier Milleron Ludivine Eliahou Marie-Sylvie Gross Nadine Hanna Catherine Boileau Laurent Gouya Guillaume Jondeau |
| author_facet | Thomas Grange Mélodie Aubart Maud Langeois Louise Benarroch Pauline Arnaud Olivier Milleron Ludivine Eliahou Marie-Sylvie Gross Nadine Hanna Catherine Boileau Laurent Gouya Guillaume Jondeau |
| author_sort | Thomas Grange |
| collection | DOAJ |
| 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 <i>FBN1</i> 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. |
| first_indexed | 2024-03-10T19:43:04Z |
| format | Article |
| id | doaj.art-aaf527823a4d4e66b6e5857bb26f9b22 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T19:43:04Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-aaf527823a4d4e66b6e5857bb26f9b222023-11-20T01:07:57ZengMDPI AGGenes2073-44252020-05-0111557410.3390/genes11050574Quantifying the Genetic Basis of Marfan Syndrome Clinical VariabilityThomas Grange0Mélodie Aubart1Maud Langeois2Louise Benarroch3Pauline Arnaud4Olivier Milleron5Ludivine Eliahou6Marie-Sylvie Gross7Nadine Hanna8Catherine Boileau9Laurent Gouya10Guillaume Jondeau11INSERM U1148, 75018 Paris, FranceINSERM U1148, 75018 Paris, FranceCentre national de référence pour le syndrome de Marfan et apparentés, AP-HP, Hôpital Bichat, 75018 Paris, FranceINSERM U1148, 75018 Paris, FranceINSERM U1148, 75018 Paris, FranceCentre national de référence pour le syndrome de Marfan et apparentés, Service de cardiologie, AP-HP, Hôpital Bichat, 75018 Paris, FranceCentre national de référence pour le syndrome de Marfan et apparentés, Service de cardiologie, AP-HP, Hôpital Bichat, 75018 Paris, FranceINSERM U1148, 75018 Paris, FranceCentre national de référence pour le syndrome de Marfan et apparentés, Département de génétique, AP-HP, Hôpital Bichat, 75018 Paris, FranceINSERM U1148, 75018 Paris, FranceCentre national de référence pour le syndrome de Marfan et apparentés, AP-HP, Hôpital Bichat, 75018 Paris, FranceINSERM U1148, 75018 Paris, FranceMarfan 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 <i>FBN1</i> 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.https://www.mdpi.com/2073-4425/11/5/574marfanheritabilitymodifiersfibrillin |
| spellingShingle | Thomas Grange Mélodie Aubart Maud Langeois Louise Benarroch Pauline Arnaud Olivier Milleron Ludivine Eliahou Marie-Sylvie Gross Nadine Hanna Catherine Boileau Laurent Gouya Guillaume Jondeau Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability Genes marfan heritability modifiers fibrillin |
| 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 | marfan heritability modifiers fibrillin |
| url | https://www.mdpi.com/2073-4425/11/5/574 |
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