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.

A case of Acromicric dysplasia with FBN1 mutation / 中华内分泌代谢杂志

Acromicric dysplasia(AD) is a rare skeletal dysplasia characterized by severe short stature, short hands and feet, normal intelligence, mild facial dysmorphism, and radiological characteristics. The clinical data and genetic test results of one patient with AD in our hospital were analyzed, and the clinical characteristics of this case were summarized. The main manifestations of the child were short stature, short hands and feet, mild facial dysmorphism, short and stubby metacarpals and phalanges on hand X-ray. One mutation, FBN1: c.5141T>G(p.Met1714Arg), was identified in this child, the mutation is inherited from her short mother and grandfather. AD is a rare congenital skeletal dysplasia disorder associated with mutations in the FBN1 gene. It conforms to the pathogenesis of autosomal dominant genetic disease.

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.

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.

Mutación c.3037G>A en el gen FBN1 asociado a síndrome de Marfan variante neonatal / Mutation c.3037G>A in the FBN1 gene associated with neonatal Marfan syndrome variant

Resumen: El síndrome de Marfan ([SM], OMIM 154700) es un trastorno del tejido conectivo que exhibe un patrón de herencia autosómico dominante, cuyas características clínicas pueden afectar de forma variable múltiples sistemas u órganos. Es causado por mutaciones en el gen FBN1 (OMIM 134797) localizado en 15q21.1. El SM neonatal es una variedad infrecuente de la entidad asociado con mutaciones en el cambio de sentido entre los exones 23-33 y mutaciones truncadas, exhibe un fenotipo más severo y alto porcentaje de mortalidad en los primeros años de vida. Se presenta el caso de adolescente masculino con SM neonatal y mutaciones en el cambio de sentido (c.3037G>A; p.Gly225Arg) en el exón 24 del gen FBN1. Ante estos hallazgos se estudió la variación fenotípica interfamiliar, la evaluación médica interdisciplinaria precoz necesaria para el manejo de las posibles complicaciones, así como el oportuno asesoramiento genético familiar.

Abstract: Marfan syndrome ([MS], OMIM 154700) is a connective tissue disorder that exhibits an autosomal dominant pattern of inheritance, whose clinical characteristics can affect multiple systems or organs in a variable way. It is caused by mutations in the FBN1 gene (OMIM 134797) located at 15q21.1. Neonatal MS is an uncommon variety of the entity associated with missense mutation between exons 23-33 and truncating mutations, exhibits a more severe phenotype and high percentage of mortality in the first years of life. The case of male adolescent with neonatal MS and missense mutation (c.3037G> A; p.Gly225Arg) in exon 24 of the FBN1 gene is presented. Given these findings, interfamilial phenotype variation, the early interdisciplinary medical evaluation necessary for the management of possible complications, as well as the appropriate family genetic counseling were studied.

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.

MiR-503 promotes wound healing of diabetic foot ulcer by targeting FBN1

Objective: To highlight the relationship between miR-503 and wound healing of diabetic foot ulcer (DFU). Methods: Microarray analysis was used to detect the dysregulated miRNAs between the DFU tissues and normal tissues. The expression of miR-503 in tissues and serum of patients with DFU was detected by qRT-PCR technique. Then, CCK-8 assay was applied to determine the cell proliferation. TUNEL assay was used for assessing the apoptosis of cells after treatment with miR-503. Possible correlation between miR-503 and fbillin1 (FBN1) was predicted according to data accessed on RNA22 website online, and was detected for confirmation by luciferase reporter assay. Results: Microarray analysis showed that miR- 503 was significantly decreased in the DFU tissues compared with normal tissues. While marked increase in the expression of miR-503 in tissues and serum of patients with DFU was confirmed by qRT-PCR technique. Then, CCK-8 assay indicated that transfection of miR- 503 mimic obviously accelerated the cell proliferation. However, TUNEL assays suggested that miR-503 mimic inhibited the apoptosis of cells to improve the survival of fibroblasts. Besides, miR-503 AMO played a role in fibroblasts of DFU tissues exactly countering to miR-503 mimic treatment. It was predicted that MiR-503 is a complementary to the FBN1 by RNA22. Besides, SiRNA-FBN1 promoted the proliferation, but brought down the apoptosis of fibroblasts. Conclusions: MiR-503 regulates the function of fibroblasts and wound healing of patients with DFU by targeting FBN1 directly which provids a novel and critical target for diagnosis and treatment of DFU.

MiR-503 promotes wound healing of diabetic foot ulcer by targeting FBN1

Objective:To highlight the relationship between miR-503 and wound healing of diabetic foot ulcer (DFU).Methods:Microarray analysis was used to detect the dysregulated miRNAs between the DFU tissues and normal tissues. The expression of miR-503 in tissues and serum of patients with DFU was detected by qRT-PCR technique. Then, CCK-8 assay was applied to determine the cell proliferation. TUNEL assay was used for assessing the apoptosis of cells after treatment with miR-503. Possible correlation between miR-503 and fbillin1 (FBN1) was predicted according to data accessed on RNA22 website online, and was detected for confirmation by luciferase reporter assay.Results:Microarray analysis showed that miR- 503 was significantly decreased in the DFU tissues compared with normal tissues. While marked increase in the expression of miR-503 in tissues and serum of patients with DFU was confirmed by qRT-PCR technique. Then, CCK-8 assay indicated that transfection of miR- 503 mimic obviously accelerated the cell proliferation. However, TUNEL assays suggested that miR-503 mimic inhibited the apoptosis of cells to improve the survival of fibroblasts. Besides, miR-503 AMO played a role in fibroblasts of DFU tissues exactly countering to miR-503 mimic treatment. It was predicted that MiR-503 is a complementary to the FBN1 by RNA22. Besides, SiRNA-FBN1 promoted the proliferation, but brought down the apoptosis of fibroblasts.Conclusions:MiR-503 regulates the function of fibroblasts and wound healing of patients with DFU by targeting FBN1 directly which provids a novel and critical target for diagnosis and treatment of DFU.

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.

A c.3037G>A mutation in FBN1 gene causing Marfan syndrome with an atypically severe phenotype / Mutación c.3037G>A en el gen FBN1 causa sindrome de Marfan con fenotipo atípico severo

Marfan syndrome is a pleiotropic connective tissue disease inherited as an autosomal dominant trait, mostly caused by mutations in the FBN1 gene, which is located on chromosome 15q21.1 and encoding fibrillin 1. We report a case of Marfan syndrome presen ting with severe ocular and systemic manifestations, such as cardiac congenital anomalies. The patient underwent a multidisciplinary approach and his clinical diagnosis was associated with a c.3037G>A mutation in the FBN1 gene. Identification of this genetic alteration should instigate a prompt multidisciplinary assessment and monitoring, in order to prevent devasta ting consequences such as cardiac and ocular phenotype. Molecular modeling of the mutation highlighted the importance of the preservation of the calcium-dependent structure of an epidermal-growth-factor-like domain of fibrillin-1 and consequently the microfibrillar formation process. This report aims to highlight the importance of an early clinical and molecular diagnosis and once more, the importance of the multidisciplinary approach of this genetic entity.

El síndrome de Marfan es una enfermedad pleitrópica del tejido conjuntivo que exhibe un patrón de herencia autosómico dominante, en su mayoría causado por mutacio nes en el gen FBN1 , que se encuentra en el cromosoma 15q21.1 y codifica a la fibrilina 1. Se presenta un caso de síndrome de Marfan que cursa con manifestación sistémica severa cardíaca y principlamente ocular. El paciente presentó una valoración multidisciplinaria y su diagnóstico clínico fue asociado con la mutación c.3037G>A en el gen FBN1 . La identificación de esta alteración genética debe promover una pronta evaluación y supervisión con el fin de evitar las desvastadoras consecuencias, tales como el fenotipo cardíaco y ocular. El modelado comparativo de proteínas resalta la importancia de la conservación de la estructura del dominio de la fibrilina-1 dependiente de calcio similar al factor de crecimiento epidérmico y por lo tanto el proceso de formación microfibrilar. Este informe tiene como objetivo resaltar la importancia de un diagnóstico clínico y molecular temprano y el enfoque multidisciplinariode esta entidad genética.

Bilateral Simple Ectopia Lentis Associated with FBN1 Gene Mutation

PURPOSE: To report a case of bilateral simple ectopia lentis associated with FBN1 gene mutation. CASE SUMMARY: A 47-year-old women presented with a one-month history of ocular pain and decreased visual acuity of the right eye. She had a family history of crystalline lens dislocation but showed no systemic abnormality or trauma history. Intraocular pressure was 45 mmHg in the right eye, which showed a myopic shift (−6.5 D). The crystalline lens of the right eye was subluxated to the anterior chamber, and the angle was closed. Phacoemulsification with scleral fixation of the posterior chamber intraocular lens of the right eye was performed. After that, best corrected visual acuity of the right eye was 1.0, and intraocular pressure was 15 mmHg. After 2 years, she presented with intermittent ocular pain and decreased visual acuity of the left eye. The crystalline lens of the left eye was subluxated to the anterior chamber. Phacoemulsification with scleral fixation of the posterior chamber intraocular lens of the left eye was performed. After that, intermittent ocular pain and visual acuity of the left eye were improved. Genetic testing confirmed an FBN1 gene mutation in the patient. CONCLUSIONS: A bilateral ectopia lentis patient without history of definite trauma should undergo complete systemic and ophthalmic examination to rule out accompanying disease, and a detailed family history should be collected. If hereditary ectopia lentis is suspected, genetic testing of probands and their family should be performed and will be helpful for genetic counseling and ophthalmic surveillance.

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.

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.

A novel FBN1 gene mutation associated with early-onset pneumothorax in Marfan syndrome

Marfan syndrome (MFS) is an inherited connective tissue disorder with a mutation in the fibrillin-1 (FBN1) gene. Fibrillin is a major building block of microfibrils, which constitute the structural component of the connective tissues. A 10-year-old girl visited our hospital with the chief complaint of precocious puberty. According to her medical history, she had a pulmonary wedge resection for a pneumothorax at 9 years of age. There was no family history of MFS. Mid parental height was 161.5 cm. The patient's height was 162 cm (>97th percentile), and her weight was 40 kg (75th-90th percentile). At the time of initial presentation, her bone age was approximately 11 years. From the ophthalmologic examination, there were no abnormal findings except myopia. There was no wrist sign. At the age of 14 years, she revisited the hospital with the chief complaint of scoliosis. Her height and weight were 170 cm and 50 kg, respectively, and she had arachnodactyly and wrist sign. We performed an echocardiograph and a test for the FBN1 gene mutation with direct sequencing of 65 coding exons, suspecting MFS. There were no cardiac abnormalities including mitral valve prolapse. A cytosine residue deletion in exon 7 (c.660delC) was detected. This is a novel mutation causing a frameshift in protein synthesis and predicted to create a premature stop codon. We report the case of a patient with MFS with a novel FBN1 gene missense mutation and a history of pneumothorax at a young age without cardiac abnormalities during her teenage years.

Analysis of Protrusio Acetabuli Using a CT-based Diagnostic Method in Korean Patients with Marfan Syndrome: Prevalence and Association with Other Manifestations

A new CT-based diagnostic method of protrusio acetabuli (PA) was introduced. However, prevalence of PA by this method and correlation between PA and other manifestations of Marfan syndrome (MFS) is unknown in Korean MFS patients. This study aimed to investigate the prevalence of PA diagnosed by a CT-based method in Korean patients with MFS, the association of PA with other manifestations of MFS, and the contribution of PA to MFS diagnosis. We retrospectively reviewed the records of 146 MFS patients with the presence of a causative FBN1 mutation and 146 age- and sex-matched controls from a single tertiary care center. All MFS patients underwent a complete assessment of criteria based on the revised Ghent nosology. PA was assessed quantitatively using a CT-based circle-wall distance (CWD) method. PA was diagnosed in 77.4% of patients in the MFS group and in 11.0% of the control group. CWD was significantly different between the two groups (1.50 mm vs. -0.64 mm, P<0.001). The presence of PA did not correlate with the presence of ectopia lentis, aortic root diameter, or history of aortic dissection. The presence of PA did not have a significant impact on the final diagnosis of MFS. Even though the presence of PA does not related to the cardinal clinical features of MFS or influence MFS diagnosis, its presence may be helpful for the suspicion of MFS when aortic dissection or aneurysm is found on CT angiography of the aorta because of the high frequency of PA in MFS patients.

Síndrome de Marfan, mutaciones nuevas y modificadoras del gen FBN1 / Síndrome de Marfan, mutaciones nuevas y modificadoras del gen FBN1

El síndrome de Marfan (SM) es un trastorno sistémico causado por mutaciones en la proteína de la matriz extracelular fibrilina 1 (FBN1). Con un patrón de herencia autosómico dominante, los pacientes se caracterizan por presentar compromiso ocular, cardiovascular y esquelético dentro de un espectro clínico variable. Se ha sugerido que la variabilidad fenotípica intrafamiliar e interfamiliar característica del síndrome ocurre por la asociación de otras mutaciones denominadas modificadoras (driver mutations). Si bien hay claridad acerca de la causalidad genética clásica de la enfermedad, las mutaciones modificadoras descritas recientemente aún no están bien dilucidadas. Se presenta un caso de SM con una mutación no descrita previamente en el gen de la fibrilina 1; se aplica la nosología de Ghent revisada y se analiza el papel de esta mutación nueva y de las mutaciones modificadoras en la génesis de la enfermedad.

Marfan syndrome (MS) is a systemic disorder caused by mutations in the extracellular matrix protein fibrillin 1 (FBN1). With a dominant autosomal pattern, MS patients are characterized by ocular, cardiovascular and skeletal involvement, all within a variable clinical spectrum. It has been suggested that the intrafamilial and interfamilial phenotypic variability, characteristic of the syndrome, occurs by the association of other mutations called driver mutations. Even though there is a clear genetic causation, the recently described driver mutations are not yet fully elucidated. We present a MS case with a mutation not previously described in the fibrilin 1 gene, applying the revised Ghent nosology and analyzing the role of this new mutation and of the driver mutations in the genesis of the disease.

Novel CHD7 and FBN1 mutations in an infant with multiple congenital anamolies.

The first case of an infant with a dual genetic diagnosis of CHARGE and Marfan syndrome is reported here. The patient had multiple congenital anamolies, many of them consistent with CHARGE syndrome and genetic testing identified a heterozygous mutation c.3806_11del6insA in the CHD7 gene. In addition, his father had physical features consistent with Marfan syndrome. Fibrillin-1 (FBN1) mutation screening identified a heterozygous c.3990insC mutation in both father and the patient.