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*

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

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 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 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

Adolescent ; Adult ; Female ; Fibrillins ; Humans ; Male ; Marfan Syndrome ; diagnosis ; genetics ; Microfilament Proteins ; genetics ; Young Adult

Patients with Marfan syndrome (MFS) presents with primary skeletal manifestations such as tall stature, chest wall abnormality, and scoliosis. These primary skeletal manifestations affect the growth pattern in MFS. Therefore, it is not appropriate to use normal growth charts to evaluate the growth status of MFS. We aimed to develop disease-specific growth charts for Korean MFS patients and to use these growth charts for understanding the growth patterns in MFS and managing of patients with MFS. Anthropometric data were available from 187 males and 152 females with MFS through a retrospective review of medical records. Disease-specific growth charts were generated and 3, 25, 50, 75, and 97 percentiles were calculated using the LMS (refers to lambda, mu, and sigma, respectively) smoothing procedure for height and weight. Comparisons between MFS patients and the general population were performed using a one-sample t-test. With regard to the height, the 50th percentile of MFS is above the normative 97th percentile in both genders. With regard to the weight, the 50 percentile of MFS is above the normative 75th percentile in male and between the normative 50th percentile and the 75th percentile in female. The disease-specific growth charts for Korean patients with MFS can be useful for monitoring growth patterns, planning the timing of growth-reductive therapy, predicting adult height and recording responses to growth-reductive therapy.
Adolescent ; Adult ; Asian Continental Ancestry Group ; *Body Height ; Body Mass Index ; *Body Weight ; Child ; Child, Preschool ; Female ; *Growth Charts ; Growth Disorders/*physiopathology ; Humans ; Male ; Marfan Syndrome/genetics/*physiopathology ; Microfilament Proteins/genetics ; Reference Values ; Republic of Korea ; Retrospective Studies ; Young Adult

OBJECTIVETo screen for mutations of fibrillin-1 (FBN1) gene in 4 patients with Marfan syndrome in order to provide prenatal diagnosis and genetic counseling.

METHODSPotential mutations of the FBN1 gene in the probands were detected with PCR and DNA sequencing. Subsequently, genomic DNA was extracted from amniotic fluid sampled between 18 to 20 weeks gestation. The mutations were confirmed with denaturing high-performance liquid chromatography - robust microsatellite instability (DHPLC-MSI) analysis with maternal DNA as reference. The products were further analyzed by direct sequencing and BLAST search of NCBI database.

RESULTSAn IVS46+1G>A substitution was identified in patient A at +1 position of intron 46 of the FBN1 gene. Two novel missense mutations were respectively discovered at positions +4453 of intron 35 in patient B (Cys1485Gly) and position +2585 of intron 21 in patient C (Cys862Tyr). In patient D, a novel deletion (c.3536 delA) was found at position +3536 of intron 28. In all of the 4 cases, the same mutations have been identified in the fetuses.

CONCLUSIONFBN1 gene analysis can provide accurate diagnosis of Marfan syndrome, which can facilitate both prenatal diagnosis and genetic counseling.

Adult ; Base Sequence ; DNA Mutational Analysis ; Female ; Fibrillin-1 ; Fibrillins ; Humans ; Introns ; Male ; Marfan Syndrome ; diagnosis ; embryology ; genetics ; Microfilament Proteins ; genetics ; Molecular Sequence Data ; Mutation, Missense ; Pregnancy ; Prenatal Diagnosis ; Sequence Deletion

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

The Mediator Complex plays key roles in activating gene transcription in eukaryotes. Mediator of RNA polymerase II transcription subunit 12 homolog (MED12) is a subunit of the Mediator Complex and regulates the activity of the complex. MED12 is involved in a variety of cellular activities, and mutations in MED12 gene impair MED12 activities and are associated with several diseases, including Opitz-Kaveggia syndrome, Lujan syndrome, uterine leiomyomas and prostate cancer. This review will discuss the biological function of MED12 and the relationship between MED12 mutations and diseases.
Agenesis of Corpus Callosum ; genetics ; Anus, Imperforate ; genetics ; Constipation ; genetics ; Craniofacial Abnormalities ; genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Leiomyoma ; genetics ; Male ; Marfan Syndrome ; genetics ; Mediator Complex ; genetics ; metabolism ; Mental Retardation, X-Linked ; genetics ; Muscle Hypotonia ; congenital ; genetics ; Mutation ; Prostatic Neoplasms ; genetics ; Transcription, Genetic ; Uterine Neoplasms ; genetics