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Undescribed mutations in FBN1 gene in two family cases of Marfan syndrome.

ABSTRACT: Marfan syndrome (MFS) is a multisystem autosomal dominant heritable disorder and, although there are over 1700 mutations that have been identified in the fibrillin-1 (FBN1) gene associated with it, there are many variants that remain unknown. Here we report two family cases of MFS with two new undescribed variations (C914S and H2426C) in FBN1 gene. Both variations produce alterations in the structural conformation of the protein resulting in pathogenic events in these patients. Finally, this case report includes both pathogenic mutations that have also been clinically and genetically confirmed to result in MFS. This clinical, genetic, and in silico analysis of potentially harmful variations in unrelated MFS patients provides additional evidence for the suggested causative role of the mutations c.2740T > A (C914S), c.7276_7278delCAT (p.H2426C) in FBN1 gene in MFS. .

SUBMITTER: Cabrera-Bueno F

PROVIDER: S-EPMC6279638 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Undescribed mutations in FBN1 gene in two family cases of Marfan syndrome.

Cabrera-Bueno Fernando F Fernandez-Rosado Francisco F Alvarez-Cubero Maria Jesus MJ Martinez-Espin Esther E Entrala-Bernal Carmen C

Journal of cardiology cases 20140926 6

Marfan syndrome (MFS) is a multisystem autosomal dominant heritable disorder and, although there are over 1700 mutations that have been identified in the fibrillin-1 (FBN1) gene associated with it, there are many variants that remain unknown. Here we report two family cases of MFS with two new undescribed variations (C914S and H2426C) in FBN1 gene. Both variations produce alterations in the structural conformation of the protein resulting in pathogenic events in these patients. Finally, this cas ...[more]

PMID: 30534251

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Two novel mutations of FBN1 in Jordanian patients with Marfan syndrome.

Project description:Marfan syndrome is an autosomal dominant inheritance disorder with a 1/5000-live-birth prevalence. More than 3000 mutations have been characterized thus far in the FBN1 gene. The goal of this study is to facilitate Marfan syndrome diagnosis in Jordanian patients using a molecular genetic testing. All of the 65 coding exons and flanking intronic sequences of the FBN1 gene were amplified using polymerase chain reaction and were subjected to sequencing in five unrelated Jordanian patients suspected of having Marfan syndrome. Four different mutations were identified, including two novel mutations: the c.1553dupG frame-shift (p.Tyr519Ilefs*14) and the c.6650G>A (p.Cys2217Tyr) missense mutations. Two other missense mutations, c.2243G>A (p.Cys748Tyr) and c.2432G>A (p.Cys811Tyr), have been previously detected. Patient number five was heterozygous for the synonymous substitution variant c.1875T>C (p.Asn625Asn; rs#25458). Additionally, eight variants in the intronic sequence of the FBN1 gene were identified, of which the c.2168-46A>G mutation was a new variant. The data provide molecular-based evidence linking Marfan syndrome to pathogenic mutations in the FBN1 gene among Jordanians for the first time. Thus, our results will contribute to the better management of the disease using molecular tools and will help in genetic counseling of the patients' families.

| S-EPMC4694396 | biostudies-literature

Identification of FBN1 gene mutations in Ukrainian Marfan syndrome patients.

Project description:Marfan syndrome is an autosomal dominant connective tissue disorder, predominantly affecting the ocular, skeletal and cardiovascular systems. Here, we present the results of the first genetic testing in 40 Ukrainian Marfan (-like) patients and 10 relatives. We applied a targeted next generation sequencing panel comprising FBN1 and 13 thoracic aortic aneurysm genes. We identified 27 causal mutations in FBN1, obtaining a mutation yield of 67·5%. A significant difference in age at aortic surgery between mutation positive and negative patients was observed. Thus, we conclude that genetic testing is important to identify patients at higher risk for developing life-threatening cardiovascular complications.

| S-EPMC6865158 | biostudies-literature

Compound heterozygous mutations in FBN1 in a large family with Marfan syndrome.

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| S-EPMC7057098 | biostudies-literature

Next-generation sequencing identifies novel mutations in the FBN1 gene for two Chinese families with Marfan syndrome.

Project description:Marfan syndrome (MFS) is an autosomal dominant heterogeneous disorder of connective tissue characterized by the early development of thoracic aneurysms/dissections, together with defects of the ocular and skeletal systems. Loss-of-function mutations in fibrillin-1 (FBN1) encoded by the gene, FBN1 (MFS?1), and in the transforming growth factor ? receptor 2 (TGFBR2) gene, TGFBR2 (MFS?2), are major causes of this disorder. In the present study, a rapid and cost?effective method for genetically diagnosing MFS was described and used to identify disease?causing mutations in two unrelated pedigrees with MFS in mainland China. Using targeted semiconductor sequencing, two pathogenic mutations in four MFS patients of the two pedigrees were identified, including a novel frameshift insertion, p.G2120fsX2160, and a reported nonsense mutation, p.Arg529X (rs137854476), in the FBN1 gene. In addition, a rare, probably benign Chinese?specific polymorphism in the FBN1 gene was also revealed.

| S-EPMC4918605 | biostudies-literature

Novel and recurrent <i>FBN1</i> mutations causing Marfan syndrome in two Chinese families.

Project description:BackgroundTo explore the genetic defects of two families with autosomal dominant Marfan syndrome (MFS).MethodsTwo families with MFS were enrolled in this study. The detailed ocular presentations of the patients were recorded. Whole exome sequencing was performed to explore the pathogenic variants and Sanger sequencing was performed to confirm the gene mutations. Segregation analysis among the family members was made and bioinformatics analysis was performed to predict the functional impact of the mutations.ResultsThe main ocular presentations of the probands were increased axial length and ectopia lentis. Using whole exome sequencing and Sanger sequencing, a novel heterozygous missense mutation (c.5060G > C, p.Cys1687Ser) and a recurrent missense mutation (c.2168A > T, p.Asp723Val) were identified within FBN1, which were co-segregated with the MFS phenotype in the families. Evolutionary conservation analysis showed that codons 723 and 1,687 were highly conserved among several species. Functional impact predictions made using several online programs suggested that the mutations were pathogenic.ConclusionWe identified a novel and a recurrent missense mutation in FBN1 in two Chinese families with MFS using whole exome sequencing, and our bioinformatics analysis indicated that the mutations were disease-causing. Our results expand the mutation spectrum of FBN1 and could help us better understand the genetic defects of the patients with MFS.

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Characterisation of four novel fibrillin-1 (FBN1) mutations in Marfan syndrome.

Project description:Forty-four percent of the fibrillin-1 gene (FBN1) from 19 unrelated families with Marfan syndrome was screened for putative mutations by single strand conformational polymorphism (SSCP) analysis. Four novel mutations were identified and characterised in five people, three with classical Marfan syndrome (two from one family, and one from an unrelated family), one with a more severe phenotype, and one with neonatal Marfan syndrome. The base substitutions G2113A, G2132A, T3163G, and G3458A result in amino acid substitutions A705T, C711Y, C1055G, and C1152Y, respectively. C711Y, C1055G, and C1152Y lead to replacement of a cysteine by another amino acid; the latter two occur within epidermal growth factor-like motifs in exon 25 and 27, respectively. The A705T mutation occurs at exon 16 adjacent to the GT splice site. The A705T and C711Y mutations, at exon 16 and 17, respectively, are the first documented in the second transforming growth factor-beta 1 binding protein-like motif of FBN1.

| S-EPMC1050701 | biostudies-other

Identification of a novel FBN1 gene mutation in a Chinese family with Marfan syndrome.

Project description:PurposeTo identify the mutation in the fibrillin-1 gene (FBN1) in a Chinese family with Marfan syndrome (MFS).MethodsPatients and family members were given complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of six individuals in the family and 170 healthy Chinese individuals. All of the 65 coding exons and their flanking intronic boundaries of FBN1 were amplified in the proband by polymerase chain reaction and followed by direct sequencing. The mutation identified in the proband was screened in the other family members and the 170 healthy Chinese individuals by direct sequencing. Protein conservation analysis was performed in six species using an online ClustalW tool. Protein structure was modeled based on the Protein data bank and mutated in DeepView v4.0.1 to predict the functional consequences of the mutation.ResultsA novel heterozygous c.3703T>C change in exon 29 of FBN1 was detected in the proband, which resulted in the substitution of serine by proline at codon 1235 (p.S1235P). This mutation was also present in two family members but absent in the other, unaffected family members and the 170 healthy Chinese individuals. The mutant residue located in the calcium binding epidermal growth factor-like#15 domain is highly conserved among mammalian species and could probably induce conformation change of the domain.ConclusionsWe indentified a novel p.S1235P mutation in FBN1, which is the causative mutation for MFS in this family. Our result expands the mutation spectrum of FBN1 and contributes to the study of the molecular pathogenesis of Marfan syndrome.

| S-EPMC3185025 | biostudies-literature

Family-based whole-exome sequencing identifies novel loss-of-function mutations of FBN1 for Marfan syndrome.

Project description:Background:Marfan syndrome (MFS) is an inherited connective tissue disorder affecting the ocular, skeletal and cardiovascular systems. Previous studies of MFS have demonstrated the association between genetic defects and clinical manifestations. Our purpose was to investigate the role of novel genetic variants in determining MFS clinical phenotypes. Methods:We sequenced the whole exome of 19 individuals derived from three Han Chinese families. The sequencing data were analyzed by a standard pipeline. Variants were further filtered against the public database and an in-house database. Then, we performed pedigree analysis under different inheritance patterns according to American College of Medical Genetics guidelines. Results were confirmed by Sanger sequencing. Results:Two novel loss-of-function indels (c.5027_5028insTGTCCTCC, p.D1677Vfs*8; c.5856delG, p.S1953Lfs*27) and one nonsense variant (c.8034C>A, p.Y2678*) of FBN1 were identified in Family 1, Family 2 and Family 3, respectively. All affected members carried pathogenic mutations, whereas other unaffected family members or control individuals did not. These different kinds of loss of function (LOF) variants of FBN1 were located in the cbEGF region and a conserved domain across species and were not reported previously. Conclusions:Our study extended and strengthened the vital role of FBN1 LOF mutations in the pathogenesis of MFS with an autosomal dominant inheritance pattern. We confirm that genetic testing by next-generation sequencing of blood DNA can be fundamental in helping clinicians conduct mutation-based pre- and postnatal screening, genetic diagnosis and clinical management for MFS.

| S-EPMC6238762 | biostudies-literature

Identification of Novel Causal FBN1 Mutations in Pedigrees of Marfan Syndrome.

Project description:Marfan syndrome (MFS) is an autosomal dominant genetic disorder of the connective tissue, typically characteristic of cardiovascular manifestations, valve prolapse, left ventricle enlargement, and cardiac failure. Fibrillin-1 (FBN1) is the causative gene in the pathogenesis of MFS. Patients with different FBN1 mutations often present more considerable phenotypic variation. In the present study, three affected MFS pedigrees were collected for genetic analysis. Using next-generation sequencing (NGS) technologies, 3 novel frameshift pathogenic mutations which are cosegregated with affected subjects in 3 pedigrees were identified. These novel mutations provide important diagnostic and therapeutic insights for precision medicine in MFS, especially regarding the lethal cardiovascular events.

| S-EPMC5932419 | biostudies-literature

Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome.

Project description: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.

| S-EPMC8105163 | biostudies-literature

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