Advances in acromelic dysplasia caused by FBN1 mutation / 国际儿科学杂志

The mutation of FBN1 gene results in the abnormality of its encoded fibrillin-1 protein, which affects musculoskeletal growth and results in two opposing phenotypes of tall and short stature, with clinical manifestations of Marfan syndrome and acromelic dysplasia.Acromelic dysplasia caused by FBN1 mutation includes acromicric dysplasia(AD), geleophysic dysplasia(GD)and Weill-Marchesani syndrome(WMS). As some FBN1 mutations have been reported to cause both AD and GD.The dysregulation of TGF-β signal pathway is the underlying mechanism of acromelic dysplasia.Currently, there is no specific treatment, mainly symptomatic treatment, early identification, diagnosis and treatment will improve prognosis of patients.This article will review the pathogenesis, clinical phenotype, treatment and follow-up of acromelic dysplasia caused by FBN1 mutation.

Clinical laboratory genetic diagnosis of Marfan syndrome / 中华检验医学杂志

Objective:To establish the clinical laboratory genetic diagnosis procedures for Marfan syndrome (MFS) and carry out clinical laboratory genetic diagnosis for MFS families.Methods:The second generation high-throughput sequencing was used to sequence and analyze the FBN1 gene of two MFS families who visited to Fuwai Central China Cardiovascular Hospital (Heart Center of Henan People′s Hospital) from January to December 2020, and then Sanger sequencing was used to verify the second generation high-throughput sequencing results. At the same time, the sanger sequencing of mutation sites was performed on normal family members and 100 healthy people to identify the pathogenic mutations of FBN1 gene in the MFS families. The pregnant women of two families were guided for prenatal diagnosis in the second trimester of pregnancy.Results:The clinical laboratory diagnosis of MFS showed that two MFS patients had the pathogenic mutation of c.2560T>C heterozygous mutation and c.6772T>C heterozygous mutation in FBN1 gene, respectively. The mutation was not observed in 100 healthy people and normal members in two families. The prenatal diagnosis showed that there was a heterozygous mutation of FBN1 gene c.2560T>C in the first fetus of the MFS family, which was MFS. There was no mutation in the FBN1 gene in the second fetus of the MFS family, so it was recommended to continue the pregnancy. The results of postpartum follow-up were consistent with the results of clinical laboratory diagnosis.Conclusion:The clinical laboratory genetic diagnosis procedures for MFS have been established successfully, which provides an important reference for clarifying the clinical diagnosis of MFS.

FBN1 gene mutation in a Chinese pedigree of mild Geleophysic dysplasia type 2/Acromicric dysplasia and the exploration of growth-promoting therapy / 中华内分泌代谢杂志

Objective:To summarize the clinical and genetic features of 7 patients with a mild form of Geleophysic dysplasia type 2(GD2)/Acromicric dysplasia(AD) induced by fibrillin 1(FBN1) gene mutation from one Chinese family.Methods:A Chinese pedigree of mild GD2/AD treated at the Pediatric Endocrinology Department at the First Affiliated Hospital of Sun Yat-sen University between August 2017 and May 2022 was collected. Whole-exome genetic sequencing of the FBN1 gene were performed to establish the diagnosis. Additionally, a literature review was further conducted.Results:In this family, among 13 individuals spanning three generations, there were 7 affected cases, including 1 adult female, 1 adult male, and 5 children. All individuals exhibited postnatal growth failure, severe disproportionate short stature, and lacked typical facial features. Exome sequencing and Sanger sequencing confirmed the presence of a heterozygous missense mutation c. 5099A>G(p.Tyr1700Cys) in exon 42 of the FBNI gene in 6 affected individuals(Ⅱ-1, Ⅲ-1 to Ⅲ-5), which was identified as a pathogenic mutation. This mutation was previously reported in a Chinese classical achondroplasia(AD) family. Based on comprehensive genetic analysis, clinical features, and multisystem evaluation, 3 cases were diagnosed with mild type 2 growth hormone deficiency(GD2), and 4 cases were diagnosed with mild AD. Recombinant human growth hormone(rhGH; 1.1-1.4 IU·kg -1·week -1) was applied to all the 5 children, and additional gonadotropin releasing hormone analogue(GnRHa) was administered to the 2 girls in late puberty, resulting in certain growth-promoting effect. Conclusions:The c. 5099A>G(p.Tyr1700Cys) mutation not only leads to the classical type of achondroplasia(AD) as reported in the literature but also causes the non-classical GD2 or AD(mild GD2/AD). Further research is warranted to investigate the long-term therapeutic effects of rhGH treatment.

Latest advances in the diagnosis and treatment of Marfan syndrome / 中国当代儿科杂志

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.

Genotype-phenotype analysis of five families with congenital ectopia lentis accompanied with cardiovascular abnormalities / 中华实验眼科杂志

Objective To analyze the genotype-phenotype correlation in 5 families with congenital ectopia lentis (CEL) accompanied with cardiovascular abnormal manifestation.Methods Detailed clinical data of 15 family members in 5 families were collected from August 2017 to March 2018 in Zhongshan Ophthalmic Center,including examination of the condition of lens before and after mydriasis by slit-lamp,evaluation of the cardiovascular system using transthoracic echocardiography,and evaluation of the degree of involvement of the subjects' skeletal system using X-ray images.Genomic DNAs were extracted from whole blood sample of the 5 probands and 10 relatives,and screened for FBN1 mutation by targeted exome sequencing.The possible genotype-phenotype correlation was analyzed by reviewing previous literatures into these mutation sites.The study followed the principles of the Helsinki Declaration and written informed consent was obtained from each subject prior to any examination.Results All of the five probands were diagnosed as CEL accompanied with cardiovascular abnormal manifestation.FBN1 gene mutations were identified in all of the five probands,including four missense mutations (c.2741G＞T,c.2585G＞T,c.1633C＞T,c.4260C＞G) and one splicing mutation (c.2114-1G＞C).It was predicted that all of the 5 mutations would alter the protein structure.Conclusions FBN1 gene has a high degree of clinical heterogeneity,and the early detection of ocular phenotypes combined with genetic screening is of great significance in the diagnosis of cardiovascular abnormalities.

Mutation analysis of the autosomal dominant Weill-Marchesani syndrome and genotype-phenotype review / 中华实验眼科杂志

Objective To screen the disease-causing genes in an autosomal dominant (AD)Weill-Marchesani syndrome (WMS) family from Henan province in China,and to analyze the relationship between genotypes and phenotypes of the AD WMS.Methods A family with suspected WMS was collected and studied in Henan Eye Hospital from September 2016 to July 2017.Clinical data and genomic DNA of the families were analyzed and genetic variations were screened by whole-exome sequencing (WES) The candidate genes related to ectopia lentis (FBN1,ADAMTSL2,ADAMTSL4,TGFBR2,CBS,ADAMTS10,ADAMTS17) were analyzed,and multiplex ligation dependent probe amplification (MLPA) was applied.Novel variants were further evaluated by sequencing 96 normal individuals.The previous reports with similar genetic characteristics were reviewed and the mutation types and clinical features were summarized.Written informed consent was obtained from the participants or their guardians before the collection of their venous blood and clinical data.Ethical approval was obtained from the Institutional Review Board of Henan Eye Institute.Results The suspicious mutation of the c.5260G＞A was detected in exon 42 of the FBN1 by WES in this family,which was predicted to be pathogenic and cosegregated with the disease;the clinical futures of the patients in the family included proportionate short stature,brachydactyly,joint stiffness,and the ocular problems included microspherophakia,moderate myopia,secondary glaucoma.Four mutations of FBN1 that related to WMS were reported in previous literature,and three of them were located in 41-42 exons and the others were the deletion of exons 9-11.All patients had typical clinical features of microspherophakia,short stature,brachydactyly,joint stiffness.In addition,thick skin was common,heart defects were occasional,protuberant abdomen and umbilical hernia were rarely reported.Conclusions The affected members in this family are in according with the clinical and genetic diagnosis of WMS.A novel mutation (c.5260G＞A) in FBN1 is discovered,which increases the spectrum of WMS mutation.The 41-42 exons of the FBN1 are hotspot of mutation in WMS.

Clinical features of Marfan syndrome and analysis ofFBN1 gene mutation / 临床儿科杂志

Objective To explore the clinical features of Marfan syndrome (MFS) and its virulence gene mutation of FBN1.Methods Clinical data of 2 children with MFS were retrospectively analyzed, and pertinent literatures were reviewed. Results Case one was a 1 year and 10 months old boy with a special face, bilateral lower eyelid edema, high palatal arch, slender fingers and toes. A little of moist rales in lung could be heard, and systolic accentuated in apex could be heard too. Echocardiography showed that aortic coronary sinus dilated, aorta and pulmonary artery broadened, left ventricular diverticulum, a small amount of mitral regurgitation,and moderate tricuspid regurgitation. Electrocardiogram showed incomplete right bundle branch block. Gene detection found a c.3037G>A mutation (p.Gly1013Arg) inFBN1. Case two was a 12 years old slender boy with spider-like ifnger/toe, high myopia, 2/6 systolic and diastolic murmur in the ifrst and two auscultation area in aortic valves. Echocardiography showed the aortic sinus signiifcantly broadened, aortic incompetence, mild pulmonary regurgitation and left ventricular enlargement. Gene detection found heterozygous mutation of c.1876G>A (p.Gly626Arg) in FBN1, which has not been reported.Conclusion The diagnosis of MFS can be conifrmed byFBN1 gene detection. A new mutation of c.1876G>A (p.Gly626Arg) was detected.

Two de novo mutations including 1 novel mutation in FBN1 and genotype-phenotype correlation in 2 Chinese Marfan syndrome families / 中国病理生理杂志

[ ABSTRACT] AIM:To investigate the genetic cause of 2 Chinese families with Marfan syndrome .METHODS:The clinical and laboratory investigations were performed in the 2 unrelated Chinese families .Family 1 had 1 patient with cardiac problem.Family 2 had 2 patients:one died, and the other with respiratory and cardiac problems .Next generation sequencing and Sanger sequencing in the Marfan syndrome causal gene FBN1 were performed in the patient , his unaffected sister and the parents of family 1.Sanger sequencing covering all the exons and intron-exon boundaries were performed in the patient and the parents in family 2.Bioinformatic analysis was engaged in the variations unravelled .Fifty healthy indi-viduals were also investigated in the same manner .RESULTS:Both patients were diagnosed with Marfan syndrome .A no-vel mutation c.4685G>A (p.Cys1562Tyr) was detected in the patient of family 1 but was absent in his parents and the unaffected sister .This is a previously unreported novel mutation .In the mutation a conserved Cys was substituted by a Tyr in amino acid 1562 affecting a TGF-βbinding domain and the secondary structure in the encoded protein .We also detected the mutation c.3706T>C (p.Cys1236Arg) in the patient of family 2.It was absent in the unaffected parents , and there-fore was a de novo mutation too.This mutation has been previously reported and known to be associated with neonatal Marfan syndrome .Both mutations were absent in the 50 healthy controls .We also compared the genotype and phenotypes of the 2 families.CONCLUSION:We report 2 de novo mutations in 2 Chinese families with Marfan syndrome .One of the 2 mutations is novel.The phenotype of the mutation c.4685G>A(p.Cys1562Tyr) in family 1 is associated with classical Marfan syndrome, while that of c.3706T>C (p.Cys1236Arg) in family 2 is with neonatal type of Marfan syndrome .De novo mutations may be a cause for a proportion of mutations underlying the disease .The novel mutation also expends the mutational spectrum of the FBN1 gene.