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At least 19 recordsLinked to original sources
PubMed2026

A novel truncating FBN1 variant in a family with Marfan syndrome.

Marfan syndrome is caused by pathogenic variants in FBN1. We identified a novel heterozygous frameshift variant in FBN1 (NM_000138.5: c.6784_6787del, NP_000129.3:p.(Gln2262TrpfsTer28)) in an adult male with severe cardiovascular manifestations. The variant was absent from population databases and fulfilled PVS1 and PM2 criteria. This finding expands the mutational and phenotypic spectrum of FBN1 and highlights the clinical utility of genetic testing in family-based clinical management of Marfan syndrome.

Journal Article↗
PubMed1977

Cardiac, skeletal and ophthalmologic abnormalities in relatives of patients with the Marfan syndrome.

Nine patients with the Marfan syndrome and 40 of their first degree relatives were evaluated for the presence of cardiac, skeletal and ophthalmologic abnormalities. Aortic root dilatation and mitral valve prolapse were sought by echocardiography, and the metacarpal index was calculated from hand X-rays. Abnormalities of all the tests performed were present in all nine index cases, except for one normal eye exam. Mitral prolapse was present in thirteen relatives (33%) and aortic root dilatation in seven (18%). At least one cardiac abnormality was present in nineteen (47%) relatives. Aortic root dilatation was more common in male relatives; the incidence of mitral prolapse was approximately equal in the two sexes. Abnormal metacarpal index (greater than 8.0) occurred in fifteen of twenty-six relatives examined (58%). Ophthalmologic abnormalities were found in only four relatives. Two relatives had abnormalities of all three organ systems evaluated, five others had abnormalities of two systems, and fourteen had abnormalities of one system. We conclude that cardiac and skeletal abnormalities are demonstrable in a high percentage of first degree relatives of patients with the Marfan syndrome.

Adolescent↗
PubMed2025

Unraveling a novel FBN1 variant in Marfan syndrome with dilated aortic root manifestation.

BACKGROUND: Marfan syndrome (MFS) is a genetic disorder affecting connective tissue, with variable incidence rates. A significant portion of cases stems from novel genetic variants, while others inherit it from affected parents. OBJECTIVE: This study focuses on identifying the genetic cause of MFS in a specific family, using whole-exome sequencing (WES). METHODS: A 15-year-old male with confirmed MFS was examined, showing symptoms of palpitations and severe mitral valve regurgitation. WES was performed, followed by confirmation with Sanger sequencing. Variants were assessed for pathogenicity using bioinformatics tools and the American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: One potentially novel pathogenic variant was found in exon 14 of the FBN1 gene: c.1676delCinsAAT, p.Ala559GlufsTer21. In silico analysis suggested a deleterious impact on protein structure and function, supporting their pathogenic classification. CONCLUSION: The identification of this novel variant highlights the importance of the FBN1 gene in MFS, especially its cardiovascular manifestations. Early intervention can improve patient outcomes, while ongoing research holds promise for further advancements in treatment for Marfan syndrome.

Humans↗
PubMed2025

Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome.

PURPOSE: To quantify the impact of noncanonical FBN1 splice site variants in undiagnosed Marfan syndrome (MFS), a connective tissue disorder associated with skeletal abnormalities and familial thoracic aortic aneurysm disease (FTAAD). METHODS: A systematic analysis of ultrarare FBN1 variants was performed using genome sequencing data from the 100,000 Genomes Project. Variants were annotated with SpliceAI and the significance of enrichment among individuals with FTAAD was assessed using Fisher's exact test. Experimental validation used RNA sequencing, reverse transcriptase polymerase chain reaction, minigene constructs, and replication analysis was with data from UK Biobank. RESULTS: Using aggregate data for 78,195 individuals, we identified 13,864 singleton single-nucleotide variants in FBN1 of which 21 were predicted to affect splicing (SpliceAI > 0.5). Incidence of candidate splice variants in individuals recruited with FTAAD (9/703) was significantly elevated compared with that seen in non-FTAAD participants (12/77,492; odds ratio = 84, P = 9.7 × 10-14). Additional analysis uncovered a further 14 families harboring 11 different FBN1 splice variants. A total of 20 candidate splice variants in 23 families were identified, of which 70% lay beyond the ±8 splice regions. RNA testing confirmed the predicted splice aberration in 16 of 20 and for 9 of 20, pseudoexonization was the likely splicing anomaly. CONCLUSION: Our findings indicate that noncanonical splice variants may account for approximately 3% of families with undiagnosed FTAAD, highlighting the importance of incorporating analysis of introns and confirmatory RNA testing into genetic testing for Marfan syndrome.

Humans↗
PubMed1977

Probable autosomal recessive Marfan syndrome.

A probable autosomal recessive mode of inheritance is described in a family with two affected sisters. The sisters showed the typical picture of Marfan syndrome and were of normal intelligence. Both parents and all four grandparents were personally examined and found to be normal. Homocystinuria was ruled out on repeated examinations. This family suggests genetic heterogeneity in Marfan syndrome and that in some rare families the mode of inheritance may be autosomal recessive.

Child↗
PubMed1979

Cell-free synthesis of hyaluronic acid in Marfan syndrome.

The cell-free synthesis of hyaluronic acid has been demonstrated in extracts of cultured human fibroblasts. Preparations from fibroblasts of normal individuals as well as those from patients with Marfan syndrome incorporate glucuronic acid and N-acetylglucosamine from their UDP derivatives into hyaluronic acid. Extracts from Marfan fibroblasts demonstrate 3 to 10 times more total and specific hyaluronic acid synthetase activity than do preparations from normal fibroblasts. All synthetic activity was found in particulate fractions with the bulk of activity localized in material sedimenting as large membrane fragments. Marfan and normal preparations exhibited similar properties with respect to substrate, cofactor, pH requirements, and heat stability. Neither the Marfan nor normal enzyme systems could be stimulated by exogenous acceptors, nor did either preparation contain a soluble factor which stimulated or inhibited the enzymic activity of the other. The genetic defect in Marfan syndrome appears to result in increased activity of hyaluronic acid synthetase without demonstrable changes in properties of the particulate enzymes involved.

Cell-Free System↗
PubMed2025

Genotype-first assessment of presentation and penetrance of neurofibromatosis type 1, autosomal dominant polycystic kidney disease, and Marfan syndrome within the All of Us research program cohort.

PURPOSE: Phenotype-based ascertainment of probands in studies of Mendelian disorders may exclude individuals with mild phenotypes or that lack health care access. We explore this premise in All of Us Research Program participants with pathogenic variation causal for 3 Mendelian conditions: autosomal dominant polycystic kidney disease (ADPKD), Marfan syndrome, and neurofibromatosis type 1 (NF1). METHODS: We identified All of Us Research Program participants with putatively pathogenic variation in NF1, FBN1, PKD1, and PKD2. Concept terms were extracted from electronic health records to assess participant diagnosis and phenotype. Variant annotation and participant surveys were evaluated to identify biological and social factors differentiating diagnosed and undiagnosed individuals. RESULTS: Large proportions of individuals with pathogenic variation in NF1, FBN1, or PKD1/PKD2 lack the associated diagnosis of NF1 (47%), Marfan syndrome (58%), or ADPKD (52%), respectively. Pathogenic variants in diagnosed individuals have greater inferred deleteriousness for NF1 and ADPKD, and undiagnosed individuals had less severe phenotypes compared with diagnosed individuals for all 3 conditions. CONCLUSION: A genotype-first ascertainment of individuals in genomic research allows for a more comprehensive assessment of Mendelian disease and removes biases that confound our understanding of the penetrance and presentation of these conditions.

Humans↗
PubMed1979

Genetic counseling of families with Marfan syndrome and other disorders showing a Marfanoid body habitus.

Eight pedigrees of patients with Marfan syndrome are presented. In addition, four pedigrees of patients with conditions sometimes showing a marfanoid body habitus are described: Wagner-Stickler syndrome, multiple endocrine neoplasia type III, Ehlers-Danlos syndrome type VIA, and congenital contractural arachnodactyly type II. Emphasis is placed on the importance of genetic information in the differential diagnosis and management of patients and family members by the ophthalmologist.

Adolescent↗
PubMed1977

Prophylactiv use of propranolol in the Marfan syndrome to prevent aortic dissection.

Twenty-five patients, 16 men and 9 women, 5-59 years of age with the Marfan syndrome and cardiac complications were started on propranolol over a 6-year period. Propranolol was used as a beta-adrenergic blocking agent to reduce myocardial contractility in an attempt thereby to stay the progression of aortic dilatation and to prevent acute dissection of the aorta. The indications for prophylactic treatment were aortic dilatation, with aortic regurgitation in most cases. It was intended to keep the pulse rate below 70 at all times or below 60 at rest. Propranolol given in daily doses of 120-160 mg caused no side effects. The mean observation time for propranolol treatment in the 25 patients was 3.0 +/- 1.8 years ranging from 1-7 years. In spite of treatment, 5 patients (1 female and 4 males) experienced acute aortic dissection of rupture with fatal outcome. This occurred in 2 patients with the asthenic type, in 2 patients with the nonasthenic type, and in 1 patient with the marfanoid hypermobility syndrome. Serial echocardiograms showed that other patients on propranolol developed increasing dilatation of the aortic root. These observations indicate that propranolol does not necessarily protect against aortic dissection nor stop the progression of the aortic dilatation when cystic medial necrosis of the aorta is already present.

Adolescent↗
PubMed1977

Aortic lesion in Marfan syndrome: the ultrastructure of cystic medial degeneration.

Areas of medial alteration (Erdheim cystic medionecrosis) in an aortic root aneurysm surgically removed from a patient with Marfan syndrome were studied with an electron microscope. The single striking morphologic abnormality was the disorganized, haphazard architecture of the media in these areas. This lesion is interpreted as being an abortive reparative response to hemodynamic stress in a condition with a molecular defect in the structural proteins of connective tissue.

Adult↗
PubMed1978

The Marfan syndrome and cardiac surgery.

Of 31 patients with Marfan's syndrome and cardiovascular complications, 25 had ascending aortic aneurysms, five with aortic dissection; 26 had aortic regurgitation, two with aortic stenosis; and eight had mitral regurgitation, five with aortic regurgitation. Surgery included prosthetic aortic valve replacement in 24 patients and aortic valvular bicuspidization in two; 19 had resection of aneurysm with Dacron tube replacement, three had lateral aneurysmorrhaphy, and two had circumferential strip excision with end-to-end anastomosis. Four patients underwent mitral valve replacement. Operative complications occurred in 10 patients. There were nine (29 percent) hospital deaths, but only one death occurred in 12 patients operated upon since 1970. Late complications included prosthetic leak in six patients (23 percent) with reoperation in five; all survived. Five late deaths occurred (16 percent); one was unrelated and one was of unknown cause. Although risk of cardiac surgery remains high, our recent results support an aggressive surgical approach, particularly in patients with advanced or deteriorating cardiovascular complications.

Adolescent↗
PubMed1979

[Pseudoxanthoma elasticum associated with Marfan syndrome (author's transl)].

We described a 26-year-old man whose brother has a mottled fundus. Many maternal relatives suffer from myopia and heart disease, and one cousin has arachnodactylia. The patient is very tall and shows various abnormalities such as arachnodactylia, highly arched palate, funnel chest and scoliosis. He also shows hyperextensibility of joints, inguinal hernia, dissecting aneurysm of ascending aorta, dilatation of aortic ring, aortic and mitral insufficiency, myopia and striae distensae. These findings are that of Marfan's syndrome. At the same time, we noticed yellowish papules on the neck, axillae, inguinal region and inner aspect of thighs. Brown patches were found around umbilicus. These skin lesions as well as angioid streaks of fundus are typical for pseudoxanthoma elasticum. This case should be an association by chance of these two genetic affections.

Adolescent↗