Abstract
PurposeIndividuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. MethodsNext-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. ResultsThese five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. ConclusionThis underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.
Highlights
Marfan syndrome (MIM 154700, MFS) is a hereditary connective tissue disorder with an estimated incidence of 1 in 5,000 individuals
A variant can occur in a somatic cell and be contained in only a few tissues, it can occur in a germline cell, or it can occur in an early precursor cell giving a mixed somatic and germline mosaicism.[4]
The phenomenon was initially highlighted through the observation of localized or segmental forms of cutaneous diseases, such as neurofibromatosis type 1.5 Another example is Proteus syndrome, which is caused by somatic mosaicism for a pathogenic variant presumed lethal in the nonmosaic state.[6,7]
Summary
Marfan syndrome (MIM 154700, MFS) is a hereditary connective tissue disorder with an estimated incidence of 1 in 5,000 individuals. In this disease, many systems are affected with great phenotypic variability and life-threatening complications, such as the cardiovascular system, with thoracic aortic aneurysms and dissections; ocular system, with ectopia lentis; and skeletal system, with recognizable features such as scoliosis, long bone overgrowth, arachnodactyly, and pectus deformity. A clear family history is apparent in the majority of MFS probands, whereas the disease arises de novo in about 25% of the cases. The most obvious example of somatic mosaicism is cancer, but mosaicism has been described extensively in autosomal dominant diseases. The phenomenon was initially highlighted through the observation of localized or segmental forms of cutaneous diseases, such as neurofibromatosis type 1.5 Another example is Proteus syndrome, which is caused by somatic mosaicism for a pathogenic variant presumed lethal in the nonmosaic state.[6,7]
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