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Parental mosaicism in Marfan and Ehlers-Danlos syndromes and related disorders

Bertrand Chesneau^1,2, Aurélie Plancke¹, Guillaume Rolland¹

¹UF de Génétique Médicale et Cytogénétique, Centre Hospitalier Universitaire de Nîmes, Nîmes, France.

European Journal of Human Genetics : EJHG

|January 8, 2021

Abstract:

Marfan syndrome (MFS) is a heritable connective tissue disorder (HCTD) caused by pathogenic variants in FBN1 that frequently occur de novo. Although individuals with somatogonadal mosaicisms have been reported with respect to MFS and other HCTD, the overall frequency of parental mosaicism in this pathology is unknown. In an attempt to estimate this frequency, we reviewed all the 333 patients with a disease-causing variant in FBN1. We then used direct sequencing, combined with High Resolution Melting Analysis, to detect mosaicism in their parents, complemented by NGS when a mosaicism was objectivized. We found that (1) the number of apparently de novo events is much higher than the classically admitted number (around 50% of patients and not 25% as expected for FBN1) and (2) around 5% of the FBN1 disease-causing variants were not actually de novo as anticipated, but inherited in a context of somatogonadal mosaicisms revealed in parents from three families. High Resolution Melting Analysis and NGS were more efficient at detecting and evaluating the level of mosaicism compared to direct Sanger sequencing. We also investigated individuals with a causal variant in another gene identified through our "aortic diseases genes" NGS panel and report, for the first time, on an individual with a somatogonadal mosaicism in COL5A1. Our study shows that parental mosaicism is not that rare in Marfan syndrome and should be investigated with appropriate methods given its implications in patient's management.

Insights

Parental mosaicism is common in Marfan syndrome, with about 5% of FBN1 variants inherited from parents with undetected mosaicism. This finding suggests de novo events are overestimated, impacting genetic counseling for heritable connective tissue disorders.

Area of Science:

Genetics
Molecular Biology
Medical Genetics

Background:

Marfan syndrome (MFS) is a heritable connective tissue disorder (HCTD) linked to FBN1 gene variants.
Parental mosaicism, where a parent carries a genetic variant in some cells but not others, is a known phenomenon in HCTDs but its frequency in MFS is unclear.

Purpose of the Study:

To estimate the frequency of parental mosaicism in Marfan syndrome.
To investigate the role of parental mosaicism in apparently de novo FBN1 variants.
To evaluate diagnostic methods for detecting parental mosaicism.

Main Methods:

Reviewed 333 patients with disease-causing FBN1 variants.
Utilized direct sequencing, High Resolution Melting Analysis (HRMA), and Next-Generation Sequencing (NGS) to detect parental mosaicism.
Investigated mosaicism in COL5A1 variants within an aortic disease gene panel.

Main Results:

Approximately 50% of MFS cases had variants that appeared de novo, higher than the expected 25%.
Parental mosaicism was identified in 5% of FBN1 variants, meaning they were inherited, not de novo.
HRMA and NGS were more effective than Sanger sequencing for detecting and quantifying mosaicism.

Conclusions:

Parental mosaicism is a significant factor in Marfan syndrome, contributing to a higher-than-expected rate of apparent de novo mutations.
Current diagnostic approaches may underestimate the prevalence of MFS due to parental mosaicism.
Investigating parental mosaicism is crucial for accurate genetic diagnosis and family counseling in Marfan syndrome and related disorders.

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