Parental mosaicism in Marfan and Ehlers-Danlos syndromes and related disorders.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
10
04
2020
accepted:
02
12
2020
revised:
25
11
2020
pubmed:
9
1
2021
medline:
18
1
2022
entrez:
8
1
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33414558
doi: 10.1038/s41431-020-00797-3
pii: 10.1038/s41431-020-00797-3
pmc: PMC8110803
doi:
Substances chimiques
COL5A1 protein, human
0
Collagen Type V
0
FBN1 protein, human
0
Fibrillin-1
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
771-779Références
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