Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

Abstract

Purpose Individuals 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. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These 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. Conclusion This 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.

Functional Analysis of an Intronic FBN1 Pathogenic Gene Variant in a Family With Marfan Syndrome

“…Another 10%–15% of these pathogenic variants are composed of different variations of splicing errors, most of which have been reported to affect canonical splice sites at the exon/intron boundaries ( Robinson et al, 2006 ). The cryptic pathogenetic rare variants such as those located in the middle of introns that lead to the splicing of intron sequences into the FBN1 transcript, and haploinsufficiency due to small insertions, frameshift in translation, deletions and stop codons, somatic mosaicism, as well as nonsense-mediated decay of the mutated transcript, should be investigated as standard protocols for genetic diagnostic testing will not detect these mutations ( Guo et al, 2008 ; Arnaud et al, 2021 ). Furthermore, functional studies are necessary to confirm these cryptic mutations.…”

Genotype-phenotype correlations of marfan syndrome and related fibrillinopathies: Phenomenon and molecular relevance

“…Meanwhile, around 0.64% of MFS patients carried more than one FBN1 gene variant which could be overlooked in routine examinations ( Arnaud et al, 2017 ). Somatic mosaicism for a mutant FBN1 allele was associated with milder manifestations, compared to those of germ-line transmission ( Montgomery et al, 1998 ; Arnaud et al, 2021b ).…”

Cooperative Mechanism of ADAMTS/ ADAMTSL and Fibrillin-1 in the Marfan Syndrome and Acromelic Dysplasias

“…The mode of inheritance in MFS families is usually autosomal dominant. Family history is documented in approximately 65% of MFS cases ( Arnaud et al, 2021b ), while the remaining are sporadic cases. Patients with MFS usually carry heterozygous mutations in the FBN1 gene, encoding for fibrillin-1, an extracellular matrix (ECM) protein ( Collod-Béroud et al, 2003 ).…”

“…The numerous FBN1 pathogenic variants identified in MFS are located throughout the gene, with no specific clustering except for neonatal and severe forms of MFS associated with mutations within the exons 24 to 32 (called the “neonatal” region). Some cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant have been recently described ( Arnaud et al, 2021b ). Finally, rare instances of apparent autosomal recessive transmission of MFS were found to be associated with hypomorphic variants in homozygous subjects ( Arnaud et al, 2017 ).…”