Genotype–Phenotype Correlation in Children: The Impact of FBN1 Variants on Pediatric Marfan Care

Stark, V.; Hensen, Flemming; Kutsche, Kerstin; Kortüm, Fanny; Olfe, J.; Wiegand, Peter; Kodolitsch, Yskert Von; Kozlik‐Feldmann, Rainer; Müller, Götz; Mir, Thomas S.

doi:10.3390/genes11070799

Cited by 17 publications

(13 citation statements)

References 55 publications

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“…Taniguchi et al dissect the genotype-phenotype correlations in MFS already having scoliosis and found that HI variants and variants in the neonatal region were associated with severe scoliosis and faster progression ( Taniguchi et al, 2021 ). Higher systematic scores were observed in the HI group than that in the DN group ( Stark et al, 2020 ). Striae, the stretch marks of the skin, appeared more frequently in patients with HI variants ( Faivre et al, 2007 ).…”

Section: Genotype and Clinical Manifestationsmentioning

confidence: 79%

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

2022

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Marfan syndrome (MFS, OMIM: 154700) is a heritable multisystemic disease characterized by a wide range of clinical manifestations. The underlying molecular defect is caused by variants in the FBN1. Meanwhile, FBN1 variants are also detected in a spectrum of connective tissue disorders collectively termed as ‘type I fibrillinopathies’. A multitude of FBN1 variants is reported and most of them are unique in each pedigree. Although MFS is being considered a monogenic disorder, it is speculated that the allelic heterogeneity of FBN1 variants contributes to various manifestations, distinct prognoses, and differential responses to the therapies in affected patients. Significant progress in the genotype–phenotype correlations of MFS have emerged in the last 20 years, though, some of the associations were still in debate. This review aims to update the recent advances in the genotype-phenotype correlations of MFS and related fibrillinopathies. The molecular bases and pathological mechanisms are summarized for better support of the observed correlations. Other factors contributing to the phenotype heterogeneity and future research directions were also discussed. Dissecting the genotype-phenotype correlation of FBN1 variants and related disorders will provide valuable information in risk stratification, prognosis, and choice of therapy.

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Section: Genotype and Clinical Manifestationsmentioning

confidence: 79%

“…Variants in exons 24–32 were associated with ventricular tachycardia ( Aydin et al, 2013 ). Earlier onset of pulmonary artery dilatation was found in MFS children with DN variants ( Stark et al, 2020 ).…”

Section: Genotype and Clinical Manifestationsmentioning

confidence: 97%

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

2022

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“…Similarly, when genotype–phenotype correlations were assessed in a pediatric cohort, missense variants affecting a cysteine showed a higher rate of sinuses of Valsalva dilation than missense mutations not affecting cysteine. However, no differences in cardiovascular involvement were observed when comparing the other mutation types [ 81 ].…”

Section: Genotype–phenotype Correlationsmentioning

confidence: 99%

Potential predictors of severe cardiovascular involvement in Marfan syndrome: the emphasized role of genotype–phenotype correlations in improving risk stratification—a literature review

Stengl

Ágg

Pólos

et al. 2021

Orphanet J Rare Dis

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Background Marfan syndrome (MFS) is a genetically determined systemic connective tissue disorder, caused by a mutation in the FBN1 gene. In MFS mainly the cardiovascular, musculoskeletal and ocular systems are affected. The most dangerous manifestation of MFS is aortic dissection, which needs to be prevented by a prophylactic aortic root replacement. Main body The indication criteria for the prophylactic procedure is currently based on aortic diameter, however aortic dissections below the threshold defined in the guidelines have been reported, highlighting the need for a more accurate risk stratification system to predict the occurrence of aortic complications. The aim of this review is to present the current knowledge on the possible predictors of severe cardiovascular manifestations in MFS patients, demonstrating the wide range of molecular and radiological differences between people with MFS and healthy individuals, and more importantly between MFS patients with and without advanced aortic manifestations. These differences originating from the underlying common molecular pathological processes can be assessed by laboratory (e.g. genetic testing) and imaging techniques to serve as biomarkers of severe aortic involvement. In this review we paid special attention to the rapidly expanding field of genotype–phenotype correlations for aortic features as by collecting and presenting the ever growing number of correlations, future perspectives for risk stratification can be outlined. Conclusions Data on promising biomarkers of severe aortic complications of MFS have been accumulating steadily. However, more unifying studies are required to further evaluate the applicability of the discussed predictors with the aim of improving the risk stratification and therefore the life expectancy and quality of life of MFS patients.

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“…There is a specific guideline for the interpretation of sequenced variants in the FBN1 Gene for Marfan Syndrome besides the American College of Medical Genetics (ACMG) guideline to help us identify novel mutations in FBN1 likely to cause MFS (Muiño-Mosquera et al, 2018). With the identification of FBN1 as the genetic basis of MFS (Stark et al, 2020), the hope for MFS patients' early diagnosis, preventive treatment, and elective surgery is feasible.…”

Section: Introductionmentioning

confidence: 99%

Classification and Interpretation for 11 FBN1 Variants Responsible for Marfan Syndrome and Pre-implantation Genetic Testing (PGT) for Two Families Successfully Blocked Transmission of the Pathogenic Mutations

Chen

Fei

Zhang

et al. 2021

Front. Mol. Biosci.

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Background: The lifespan of Marfan Syndrome (MFS) patients is shortened, especially in patients without early diagnostics, preventive treatment, and elective surgery. Clinically, MFS diagnosis is mainly dependent on phenotypes, but for children, sporadic cases, or suspicious MFS patients, molecular genetic testing, and mainly FBN1 mutation screening, plays a significant role in the diagnosis of MFS. PGT-M gives couples that had a family history of monogenic disorders the opportunity to avoid the occurrence of MFS.Methods: In this study, 11 families with MFS were recruited and complete clinical features were collected. Variants were classified and interpreted through pedigree analysis according to guidelines. Two families chose to undergo PGT-M; 16 blastocysts were biopsied and amplified. Haplotype analysis was performed to deduce the embryo’s genotype by using single nucleotide polymorphisms (SNPs) identified in each sample.Results: We identified 11 potential disease-causing FBN1 variants, six of which are novel. All variants were assessed with prediction tools to assess mutation pathogenicity, population databases to evaluate population allele frequency, literature databases to identify whether the variant had been reported in MFS patients, and multiple sequence alignment to carry out conservative analysis. Finally, nine variants were classified as likely pathogenic/pathogenic variants. Among 11 variants, eight variants were missense, and seven of them were located in the Ca-binding EGF-like motifs, moreover, half of them substituted conserved Cysteine residues. We also identified a splice site variant, a frameshift variant, and a synonymous variant. There are two variants that are de novo variants. PGT-M helped two MFS families give birth to a healthy baby not carrying the FBN1 mutation.Conclusions: In the present study, the FBN1 mutation spectrum was enriched, and may help further elucidate the pathogenesis, benefiting clinical diagnosis and management of MFS. We make use of a reliable PGT-M method for the successful birth of healthy babies to two MFS families.

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Genotype–Phenotype Correlation in Children: The Impact of FBN1 Variants on Pediatric Marfan Care

Cited by 17 publications

References 55 publications

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

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

Potential predictors of severe cardiovascular involvement in Marfan syndrome: the emphasized role of genotype–phenotype correlations in improving risk stratification—a literature review

Classification and Interpretation for 11 FBN1 Variants Responsible for Marfan Syndrome and Pre-implantation Genetic Testing (PGT) for Two Families Successfully Blocked Transmission of the Pathogenic Mutations

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