Marfan syndrome (MFS) is a multisystem connective tissue disease with autosomal dominant inheritance. It is mainly caused by FBN1 gene mutation and often has different clinical manifestations. Neonatal MFS is especially rare with severe conditions and a poor prognosis. At present, there is still no radical treatment method for MFS, but early identification, early diagnosis, and early treatment can effectively prolong the life span of patients. This article reviews the latest advances in the diagnosis and treatment of MFS.
Fibrillin-1/genetics* ; Humans ; Infant, Newborn ; Marfan Syndrome/therapy* ; Mutation

OBJECTIVE: To detect mutations of fibrillin-1 (FBN1) gene in two pedigrees affected with Marfan syndrome (MFS). WETHODS: Peripheral blood samples were collected from MFS patients and their healthy family members for extracting genomic DNA. All of the 65 exons of the FBN1 gene were analyzed by next-generation sequencing. PolyPhen-2 and SIFT was used to predict structural and functional changes in FBN1 protein. RESULTS: Patients from both pedigrees presented ocular and skeletal manifestations suggestive of MFS. Two novel heterozygous mutations of the FBN1 gene, including c.1879C>T (p.R627C) in exon 16 and c.2584T>C (p.C862R) in exon 22, were identified. The same mutations were not found among unaffected members. By bioinformatic analysis, the mutations may affect the structure and function of the FBN1 protein. CONCLUSION The c.1879C>T and c.2584T>C mutations of the FBN1 gene probably account for the disease in the two pedigrees, respectively. Identification of the c.2584T>C has enriched the spectrum of FBN1 gene mutations.
DNA Mutational Analysis ; Exons ; Fibrillin-1 ; genetics ; Fibrillins ; Humans ; Marfan Syndrome ; genetics ; Mutation ; Pedigree

OBJECTIVE: To carry out genetic testing for a child with Marfan syndrome (MFS) and explore its genotype-phenotype correlation. METHODS: Peripheral blood samples of the child and his parents were collected for the extraction of genomic DNA and subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing. Functional impact of the variant was predicted by using bioinformatic software. RESULTS: The child, a 13-year-old male, has featured Marfanoid habitus, with arm span exceeding his height, tapering fingers and toes, pectus excavatum and scoliosis, but absence of typical cardiovascular system diseases such as aortic dilation, thoracic-abdominal aortic aneurysm, mitral valve prolapse, and lens dislocation. The child has harbored a novel splice site variant c.7383_7413del (p. N2461Kfs*211) of the FBN1 gene, which was not found in his parents and younger brother. The variant was unreported previously. CONCLUSION The novel variant of p. N2461Kfs*211 of the FBN1 gene probably underlay the MFS in this child. Above finding has enriched the genotypic and phenotypic spectrum of MFS.
Male ; Humans ; Marfan Syndrome/genetics* ; Fibrillin-1/genetics* ; Mutation ; Genotype ; Genetic Association Studies

BACKGROUNDMutations in the fibrillin-1 gene have been identified in patients with Marfan syndrome (MFS). This study aimed to identify the molecular defects in the fibrillin-1 gene in a Chinese family with Marfan syndrome, accompanied by aortic aneurysms/dissection.

METHODSTwo patients and one non-carrier in the family underwent complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of these individuals in the family as well as 50 healthy normal controls. Polymerase chain reaction amplification and direct sequencing of all 65 coding exons of fibrillin-1 gene were analyzed.

RESULTSWe found a novel mutation (c.8547T > G, p.Tyr2849X) in exon 65 of fibrillin-1 gene in a Chinese proband with Marfan syndrome, accompanied by aortic aneurysms/dissection. Sudden death at a young age of affected members was seen due to aortic aneurysms/dissection. By evaluating genotype-phenotype correlations of patients with mutations in the 3' end of fibrillin-1 gene (exons 64 and 65), we also found that the presence of nonsense mutations occurring in exons 64 and 65 appeared to be an indicator of early-onset aortic risk and sudden death.

CONCLUSIONSThese results expand the mutation spectrum of fibrillin-1 gene and help in the study of the molecular pathogenesis of Marfan syndrome, indicating that mutations occurring in the 3' end of fibrillin-1 gene may play an independent functional role in the pathogenesis of Marfan syndrome.

Adult ; Female ; Fibrillin-1 ; Fibrillins ; Genotype ; Humans ; Male ; Marfan Syndrome ; etiology ; genetics ; Microfilament Proteins ; genetics ; Middle Aged ; Mutation ; Phenotype

OBJECTIVESTo analyze the FBN1 mutations in Chinese patients with Marfan syndrome (MFS) and to make a genetic diagnosis based on haplotype linkage analysis for MFS.

METHODSNine MFS families (17 patients) were analyzed with single strand conformation polymorphism (SSCP) and sequencing. Four primers were designed for the flanking sequences of FBN1 gene and used for haplotype-segregation analysis of MFS(B).

RESULTSSSCP band alteration was detected in the PCR products for exon 25 in MFS(A) II:1. Direct sequencing revealed a small 13 bp deletion; the deleted sequence is gccTc Tgcaccca at bases 3243-3456 of the cDNA in exon 25. This mutation was novel. MFS(B) families were analyzed using the haplotype linkage technique. The data suggested that MFS(B) families were linked to the FBN1 gene. The proband's daughter was an asymptomatic patient.

CONCLUSIONThe combination of mutation detection and chromosome haplotype analysis can provide better evidence for a genetic diagnosis of MFS.

Fibrillin-1 ; Fibrillins ; Genetic Linkage ; Haplotypes ; Humans ; Marfan Syndrome ; diagnosis ; genetics ; Microfilament Proteins ; genetics ; Mutation ; Polymorphism, Single-Stranded Conformational

OBJECTIVE: To explore the genetic basis for a child featuring unexplained rapid growth and heart malformation. METHODS: Whole exome sequencing (WES)was carried out for the patient. Suspected variant was verified by Sanger sequencing and subjected to bioinformatic analysis. RESULTS: The child was found to harbor a novel de novo c.5846_5848delATA (p. N1949del) variant in exon 48 of the FBN1 gene, which was predicted to be pathogenic by Mutation Taster. The patient was ultimately diagnosed with Marfan syndrome. CONCLUSION Above finding has enriched the spectrum of genetic variants associated with Marfan syndrome. WES has provided a powerful tool for the diagnosis of rare diseases.
Child ; Exons ; Fibrillin-1/genetics* ; Heart Defects, Congenital ; Humans ; Marfan Syndrome/genetics* ; Mutation ; Sequence Deletion ; Whole Exome Sequencing

OBJECTIVE: To explore the genetic basis for four patients suspected for Marfan syndrome (MFS). METHODS: Four male patients with suspected MFS and their family members who were treated at West China Second Hospital of Sichuan University from September 12, 2019 to March 27, 2021 were selected as the study subjects. Peripheral venous blood samples were collected from the patients and their parents or other pedigree members for the extraction of genomic DNA. Whole exome sequencing was carried out, and candidate variants were validated by Sanger sequencing. The pathogenicity of the variants was determined based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). RESULTS: Genetic testing revealed that all four patients have harbored variants of the FBN1 gene, including c.430_433del (p.His144fs) deletional variant in exon 5, c.493C>T (p.Arg165*) nonsense variant in exon 6, c.5304_5306del (p.Asp1768del) deletional variant in exon 44 and c.5165C>G (p.Ser1722Cys) missense variant in exon 42. According to the ACMG guidelines, the c.430_433del and c.493C>T were classified as pathogenic variants (PVS1+PM2_Supporting+PP4; PVS1+PS1+PS2+PM2_Supporting+PP4). c.5304_5306del and c.5165C>G were classified as likely pathogenic variants (PS2+PM2_Supporting+PM4+PP4; PS2_Moderate+PS1+PM1+PM2_Supporting). CONCLUSION The c.430_433del and c.5304_5306del variants of the FBN1 gene identified in this study were unreported previously. Above results have enriched the variation spectrum of the FBN1 gene and provided a basis for genetic counseling and prenatal diagnosis of patients with MFS and acromicric dysplasia.
Female ; Pregnancy ; Humans ; Male ; Exons ; China ; Family ; Genetic Counseling ; Genetic Testing ; Marfan Syndrome/genetics* ; Mutation ; Fibrillin-1/genetics*

Marfan syndrome is a systemic disorder of connective tissue, caused by mutations in the FBN1, TGFBR1 or TGFBR2 genes. This syndrome is characterized by involvement of three major systems, skeletal, ocular, and cardiovascular. The continuing improvements in molecular biology and increasing availability of molecular diagnosis in clinical practice allow recognition of Marfan syndrome in patients with incomplete phenotypes. Additionally, molecular analyses could also be used for preimplantation genetic diagnosis. The identification of a mutation allows for early diagnosis, prognosis, genetic counseling, preventive management of carriers and reassurance for unaffected relatives. The importance of knowing in advance the location of the putative family mutation is highlighted by its straightforward application to prenatal and postnatal screening.
Fibrillin-1 ; Fibrillins ; Humans ; Marfan Syndrome ; diagnosis ; genetics ; pathology ; Microfilament Proteins ; genetics ; Mutation ; Prenatal Diagnosis ; ethics ; methods ; Protein-Serine-Threonine Kinases ; genetics ; Receptors, Transforming Growth Factor beta ; genetics

OBJECTIVETo detect pathogenic mutations in Marfan syndrome (MFS) using an Ion Torrent Personal Genome Machine (PGM) and to validate the result of targeted next-generation semiconductor sequencing for the diagnosis of genetic disorders.

METHODSPeripheral blood samples were collected from three MFS patients and a normal control with informed consent. Genomic DNA was isolated by standard method and then subjected to targeted sequencing using an Ion Ampliseq(TM) Inherited Disease Panel. Three multiplex PCR reactions were carried out to amplify the coding exons of 328 genes including FBN1, TGFBR1 and TGFBR2. DNA fragments from different samples were ligated with barcoded sequencing adaptors. Template preparation and emulsion PCR, and Ion Sphere Particles enrichment were carried out using an Ion One Touch system. The ion sphere particles were sequenced on a 318 chip using the PGM platform. Data from the PGM runs were processed using an Ion Torrent Suite 3.2 software to generate sequence reads. After sequence alignment and extraction of SNPs and indels, all the variants were filtered against dbSNP137. DNA sequences were visualized with an Integrated Genomics Viewer. The most likely disease-causing variants were analyzed by Sanger sequencing.

RESULTSThe PGM sequencing has yielded an output of 855.80 Mb, with a > 100 × median sequencing depth and a coverage of > 98% for the targeted regions in all the four samples. After data analysis and database filtering, one known missense mutation (p.E1811K) and two novel premature termination mutations (p.E2264X and p.L871FfsX23) in the FBN1 gene were identified in the three MFS patients. All mutations were verified by conventional Sanger sequencing.

CONCLUSIONPathogenic FBN1 mutations have been identified in all patients with MFS, indicating that the targeted next-generation sequencing on the PGM sequencers can be applied for accurate and high-throughput testing of genetic disorders.

Base Sequence ; Computational Biology ; Fibrillin-1 ; Fibrillins ; Genomics ; High-Throughput Nucleotide Sequencing ; methods ; Humans ; Marfan Syndrome ; diagnosis ; genetics ; Microfilament Proteins ; genetics ; Mutation ; Semiconductors

OBJECTIVETo probe into the mechanism of fibrillin 1 in pathologic scar, by examining the expressions of fibrillin 1 and TGF-beta1 as well as their correlations in the tissues of keloid, hypertrophic scar and normal skin.

METHODSThe tissues of keloid, hypertrophic scar and normal skin were tested. RT-PCR was used to assess the mRNA expression levels of the aimed genes. The distribution of fibrillin 1 in scars and normal skin was examined by immunohistochemistry staining.

RESULTSThe mRNA level of fibrillin 1 in keloid (0.802 +/- 0.116) was increased by 218.25% (P < 0.01) than that in normal skin (0.252 +/- 0.067). The expression of the gene in hypertrophic scar (0.628 +/- 0.144) was higher by 149.21% (while, P > 0.05) than that in normal skin. The expression of TGF-beta1 in keloid and hypertrophic scar were more than that in normal skin. The expression of fibrillin 1 was related to that of TGF-beta1 positively (r = 0.820, P < 0.01). Fibrillin 1 protein was stained positively in basic membranes, endothelial cells, fibroblasts and extracellular matrix of skin tissues. In dermal, the protein levels of fibrillin 1 in keloid (0.117 +/- 0.042) was decreased than those in normal skin (0.185 +/- 0.043) and hypertrophic scar (0.181 +/- 0.048), the inhibition rates were 36.76%, 35.36% respectively (both P < 0.01).

CONCLUSIONSThe expression of fibrillin 1 in keloid was changed and related to the expression of TGF-beta1 positively, which appears that fibrillin 1 was a cicatrix specific gene. Fibrillin 1 might play an important role in the formation of keloid.

Cicatrix, Hypertrophic ; metabolism ; pathology ; Fibrillin-1 ; Fibrillins ; Humans ; Keloid ; metabolism ; pathology ; Microfilament Proteins ; metabolism ; RNA, Messenger ; genetics ; Transforming Growth Factor beta1 ; genetics ; metabolism