Novel Marfan Syndrome-Associated Mutation in the FBN1 Gene Caused by Parental Mosaicism and Leading to Abnormal Limb Patterning

Martínez‐Quintana, Efrén; Caballero‐Sánchez, Noemí; Rodríguez‐González, Fayna; Garay-Sánchez, Paloma; Tugores, Antonio

doi:10.1159/000467909

Cited by 9 publications

(11 citation statements)

References 28 publications

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“…On the other hand, in one of the two parents, the disease-causing variant can appear during gametogenesis (germline or gonadal mosaicism) or, in the same way, during the early stages of the embryologic development affecting both soma and germ cells (somatogonadal mosaicism). This last mechanism, which has been previously reported in MFS [ 5 – 9 ] induces a risk of recurrence in siblings of an apparently sporadic proband [ 6 ]. Parental molecular analysis revealed the majority of reported individuals with post-zygotic mosaicisms in FBN1 .…”

Section: Introductionmentioning

confidence: 63%

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

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 63%

“…Parental molecular analysis revealed the majority of reported individuals with post-zygotic mosaicisms in FBN1 . Despite the fact that most patients with proven somatogonadal mosaic were asymptomatic or displayed discrete MFS signs [ 5 , 8 ], some of them displayed aortic dilatation [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…In our experience and in the literature, individuals harboring mosaic pathogenic variants in the FBN1 gene are usually asymptomatic. 2,[18][19][20][21][22][23] As a precaution, a follow-up in cardiology is recommended for these patients. In the literature, mosaicism is a very rare event in MFS patients since only two reports mention symptomatic probands mosaic for a FBN1 pathogenic variant.…”

Section: Discussionmentioning

confidence: 99%

Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

Arnaud

Morel

Gouya

et al. 2021

Genetics in Medicine

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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.

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“…The FBN1 protein contains a number of repeated structural modules, mostly represented by the epidermal growth factor-like calcium-binding domain (EGF_CA). Biochemical evidences show that these cysteine residues are necessary for proper folding and calcium binding of the EGF_CA module, which in turn participates in proper secretion and deposition of FBN1 [44]. In a couple of studies, aortic dissection appeared to be more common in subjects carrying a premature termination variant, compared with individuals having a cysteine substitution [41,45].…”

Section: Discussionmentioning

confidence: 99%

NGS analysis in Marfan syndrome spectrum: Combination of rare and common genetic variants to improve genotype-phenotype correlation analysis

et al. 2019

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The diagnosis of Marfan spectrum includes a large number of clinical criteria. Although the identification of pathogenic variants contributes to the diagnostic process, its value to the prediction of clinical outcomes is still limited. An important novelty of the present study is represented by the statistical approach adopted to investigate genotype-phenotype correlation. The analysis has been improved considering the extended genetic information obtained by Next Generation Sequencing (NGS) and combining the effects of both rare and common genetic variants in an inclusive model. To this aim a cohort of 181 patients were analyzed with a NGS panel including 11 genes associated with Marfan spectrum. The genotype-phenotype correlation was also investigated considering the possibility to predict presence of a pathological mutation in Marfan syndrome (MFS) main genes based only on the analysis of phenotypic traits. Results obtained indicate that information about clinical traits can be summarized in a new variable that resulted significantly associated with the probability to find a pathological mutation in MFS main genes. This is important since the choice of the genetic test is often influenced by the phenotypic characterization of patients. Moreover, both rare and common variants were found to significantly contribute to clinical spectrum and their combination allowed to increase the percentage of phenotype variability that could be explained based on genetic factors. Results highlight the opportunity to take advantage of the overall genetic information obtained by NGS data to have a better clinical classification of patients.

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Novel Marfan Syndrome-Associated Mutation in the FBN1 Gene Caused by Parental Mosaicism and Leading to Abnormal Limb Patterning

Cited by 9 publications

References 28 publications

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

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

Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

NGS analysis in Marfan syndrome spectrum: Combination of rare and common genetic variants to improve genotype-phenotype correlation analysis

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