Marfan syndrome what kind of mutation

Orphanet J Rare Dis. Article Google Scholar. Effect of mutation type and location on clinical outcome in 1, probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet. Loeys-Dietz syndrome: a primer for diagnosis and management.

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Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome To cite this version: HAL Id : hal Homozygous and compound heterozygous mutations in the gene: heterozygous unexpect.

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Download references. The authors would like to thank the community of the Hungarian Marfan syndrome patients. We also thank the members of the Hungarian Marfan Foundation for their support. You can also search for this author in PubMed Google Scholar. RS participated in the genetic testings, patient examinations, data collection, analysis and interpretation of data, performed the statistical analysis and drafted the manuscript.

AB, HA, DCS carried out genetic testings, participated in the analysis and interpretation of data and drafted the manuscript. MJM and BF carried out genetic counselling and drafted the manuscript. ZS and KB participated in patient selection, coordinated the study and established the study design.

All authors read and approved the final manuscript. Correspondence to Roland Stengl. Informed written consent was obtained from the participants. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Reprints and Permissions. Stengl, R. Optimising the mutation screening strategy in Marfan syndrome and identifying genotypes with more severe aortic involvement.

Orphanet J Rare Dis 15, Download citation. Received : 07 June Accepted : 05 October Published : 15 October Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. These genotypes cause severity and worse prognosis, including increased risk for aortic surgery, aortic dissection, and mortality.

The genotype—phenotype effect was recognized as an important factor when making a diagnosis of MFS and later predictable phenotype severity as well as clinical decisions [ 6 , 7 ]. Some have argued that truncating may be associated with a milder disease course, which has long been questioned [ 8 , 9 ]. For precision medicine of prognosis and treatment of MFS patients, more studies on the genotype—phenotype effect are warranted.

Here, 3 pedigrees with MFS were selected to identify novel mutations and assess genotype—cardiovascular phenotype effects. In this study, 3 ethnic Han Chinese families were recruited in Beijing Anzhen Hospital and diagnosed as MFS according to the revised Ghent nosology [ 10 ] based on their reported family history, clinical features, and essential echocardiography examinations.

The study was approved by the ethics committee of Beijing Anzhen Hospital and performed according to the tenets of the Declaration of Helsinki. Detailed clinical information of all patients is listed in Table 1.

A specific target sequencing panel was designed for the maximum coverage mutation of MFS. Genomic DNA was nebulized before adaptor ligation. The identified mutations were further targeted for Sanger sequencing cascade testing in other family members from these 3 pedigrees, respectively.

A forecasting software, MutationTaster, was used to predict the effect of the functional importance of variation loci identified in 3 pedigrees. MutationTaster provides a probability for the alteration to be either a causative mutation or a benign polymorphism [ 11 ]. We analyzed a four-generation Marfan syndrome family composed of 9 affected members including 4 males and 5 females.

Target gene sequencing was used to detect the proband and his 8-year-old daughter, both manifesting a marfanoid aortic sinus and tall stature. Clinical data of the patients are shown in Table 1. These recommendations do not meet the formal criteria for prophylactic aortic surgery, so conservative therapy is suggested [ 12 ].

However, unexpected type A acute aortic dissection developed 2 months later Figure 2 b. Therefore, we speculated that inherited mutation in the family is responsible for a young, rapid-progressing, and extremely dangerous aortic dissection phenotype. The proband, with an average height, complained of paroxysmal chest pain and heart murmurs. Since the dilatation of the aortic root was causing aggravation and the aortic valve developed severe regurgitation, the patient underwent a surgical operation for aortic valve and mitral valve replacement.

Individual II: 6 underwent the same surgery as the proband, but with a poor prognosis Figure 2 d. Individuals I: 1 and II: 1 died due to cardiac events. Taken together, family 2 have different features on cardiovascular disorders rather than early aortic dissection. The proband individual II: 2 was a year-old woman who presented typical marfanoid cardiovascular features, facial features, and arachnodactyly, but without ectopia lentis.

The mother of the proband had a sudden death at the age of Further comparing the similarities and differences among these 3 families showed that there is no evidence of skeletal morbidity including arm span to , scoliosis, and joint hypermobility in either of the 3 families. Therefore, it is possible to propose that MFS is variable both among and within affected families in severity of cardiovascular manifestations, due to type of mutation.

A novel frameshift deletion c. According to Sakai et al. CysLeufsX2 was observed in a Marfan patient from Japan [ 13 ]. Further analysis indicated that this mutation leads to truncation of the original amino acid full-length protein to a residue protein. We used two algorithmic tools, MutationTaster and Swiss-Model, to examine the impact of this mutation. In the conservation test by MutationTaster [ 15 ], the affected residue in family 1 was revealed to be evolutionarily conserved, which implied that the alternation of amino acids in this position is likely to damage protein function.

Furthermore, the mutant tertiary structure generated by Swiss-Model predicts that the domain where the mutation is located — differs from that of the wild-type protein — Figure 4 a. Therefore, this frameshift mutation was identified as being rare, probably disease causing, which might affect protein function by influencing the structure of the FBN1 protein or the binding between calcium and the cbEGF domain.

In family 2 individuals II: 3 and IV: 2, one de novo frameshift mutation, c. This event resulted in the insertion of 2 base pairs, leading to a change from amino acids 3 to 18 and a deletion of big fragments from amino acids 19 to , which could likely damage protein function overwhelmingly.

Furthermore, MutationTaster showed this mutation to be pathogenic. Dislocated lens. Partially dislocated lens. Close sighted. Near sighted. Near sightedness. Decreased breadth of face. Decreased width of face. Funnel chest. Difficulty sleeping. Trouble sleeping. Impaired vision. Loss of eyesight. Poor vision. Attention deficit. Attention deficit disorder. Attention deficit-hyperactivity disorder. Attention deficits. Wasting syndrome. Cleft roof of mouth. Cardiac failure.

Cardiac failures. Heart failure. Long, narrow head. Tall and narrow skull. Downward slanting of the opening between the eyelids. Coughing up blood. Underdeveloped iris. Hunched back. Round back.

Decreased elbow mobility. Limited elbow mobility. Restricted elbow motion. Little lower jaw. Small jaw. Small lower jaw. Low or weak muscle tone. Muscle ache. Muscle pain. Absence of overlap of upper and lower teeth. Open bite between upper and lower teeth. Detached retina. Receding chin. Receding lower jaw. Weak chin. Weak jaw. Muscle degeneration. Muscle wasting. Displacement of one backbone compared to another. Slipped backbone. Clouding of the lens of the eye. Cloudy lens.

Inward turning cross eyed. Outward facing eye ball. Tear in inner wall of large artery that carries blood away from heart.

Bulge in wall of root of large artery that carries blood away from heart. Deep set eye. Deep-set eyes. Sunken eye. Flexed joint that cannot be straightened. Back knee. Knee hyperextension. Hammer toe. Elevated palate. Learn more.

The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health. Marfan syndrome. From Genetics Home Reference. Description Marfan syndrome is a disorder that affects the connective tissue in many parts of the body.

Frequency The incidence of Marfan syndrome is approximately 1 in 5, worldwide. Learn more about the gene associated with Marfan syndrome FBN1.

Inheritance This condition is inherited in an autosomal dominant pattern , which means one copy of the altered gene in each cell is sufficient to cause the disorder. Research Studies from ClinicalTrials. Part 1: pathophysiology and diagnosis. Nat Rev Cardiol. Epub Mar Radiol Technol. Clinical and molecular study of children with Marfan syndrome and related type I fibrillinopathies in a series of probands with pathogenic FBN1 mutations.