Article Category: Technical Report
Published Online: Sep 19, 2018
Page range: 35 - 37
DOI: https://doi.org/10.2478/ebtj-2018-0032
Keywords
© 2018 Yeltay Rakhmanov, Paolo Enrico Maltese, Carla Marinelli, Marco Castori, Tommaso Beccari, Munis Dundar, Matteo Bertelli , published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
(other synonyms: Marfan syndrome type 1)
Marfan syndrome (MFS, OMIM disease 154700) is an inherited connective tissue disorder caused by heterozygous mutations in the extracellular matrix protein fibrillin 1 (FBN1). Cardinal manifestations of MFS include aortic aneurysm, lens dislocation and long-bone overgrowth (1). A multidisciplinary approach is required for patient management. Aortic dilatation and dissection are the major issues, while cardiac valvular, ocular, skeletal and neurological involvement are significant complications (2). Periodic monitoring for aortic dilation is necessary to prevent progression to aortic dissection (3). Pharmacological strategies should be considered to reduce blood pressure to slow down the process of aortic dilation. Today a combination of drugs, aortic monitoring and heart surgery ensure MFS patients a similar life expectancy to that of healthy people (4). Surgery may also be useful for eye and skeletal anomalies.
Since MFS may present with clinical manifestations of varying severity, diagnosis is often delayed. Undiagnosed patients can have serious complications and are at risk of sudden death, usually due to aortic dissection.
Estimated prevalence of MFS is from 6 to 20 per 100,000 individuals (5). Sun et al. (6) reported a prevalence of 17.2 per 100,000 in China in 1990.
The Revised Ghent Nosology (2010) is used to diagnose MFS. It divides diagnostic manifestations into “major” and “minor” criteria. The Ghent criteria were modified when mutations in
The differential diagnosis should consider Loeys-Dietz syndromes, congenital contractural arachnodactyly/Beals syndrome, non-syndromic familial thoracic aortic disease, Ehlers-Danlos syndromes, homocystinuria caused by cystathionine β-synthase deficiency, Stickler syndrome and fragile X syndrome.
MFS has autosomal dominant inheritance. Approximately 75% of individuals with MFS have an affected parent and approximately 25% have a
Pathogenic variants may include missense, nonsense, small insertions, small deletions, small indels and gross deletions (10).
To determine the gene defect responsible for the disease;
To confirm clinical diagnosis;
To assess the recurrence risk and perform genetic counselling for at-risk/affected individuals.
The test is listed in the Orphanet database and is offered by 44 accredited medical genetic laboratories in the EU, and in the GTR database, offered by 28 accredited medical genetic laboratories in the US.
Guidelines for clinical use of the test are described in Genetics Home Reference (
In patients meeting the revised Ghent criteria and after exclusion of partially overlapping disorders, we advise Sanger sequencing for the detection of nucleotide variations in coding exons and flanking introns in the
Multiplex Ligation Probe Amplification (MLPA) is used to detect duplications and deletions in
In incomplete phenotypes that only meet some of the revised Ghent criteria or overlapping phenotypes with mixed features of MFS and other Marfan-like conditions, a wider approach with next generation resources (e.g. customized gene panels or exome analysis) may be considered in highly specialized settings.
To perform molecular diagnosis, a single sample of biological material is normally sufficient. This may be 1 ml peripheral blood in a sterile tube with 0.5 ml K3EDTA or 1 ml saliva in a sterile tube with 0.5 ml ethanol 95%. Sampling rarely has to be repeated.
Gene-disease associations and the interpretation of genetic variants are rapidly developing fields. It is therefore possible that the genes mentioned in this note may change as new scientific data is acquired. It is also possible that genetic variants today defined as of “unknown or uncertain significance” may acquire clinical importance.
Identification of a pathogenic variant in the
A pathogenic variant is known to be causative for a given genetic disorder based on previous reports, or predicted to be causative based on loss of protein function or expected significant damage to proteins or protein/protein interactions. In this way it is possible to obtain a molecular diagnosis in new/other subjects, establish the risk of recurrence in family members and plan preventive and/or therapeutic measures.
Detection of a variant of unknown or uncertain significance (
The absence of variations in the genomic regions investigated does not exclude a clinical diagnosis but suggests the possibility of:
alterations that cannot be identified by sequencing, such as large rearrangements that cause loss (deletion) or gain (duplication) of extended gene fragments;
sequence variations in gene regions not investigated by this test, such as regulatory regions (5’ and 3’ UTR) and deep intronic regions;
variations in other genes not investigated by the present test.
Unexpected results may emerge from the test, for example information regarding consanguinity, absence of family correlation or other genetically based diseases.
In autosomal dominant transmission, the probability that an affected carrier transmit the variant to his/her children is 50% in any pregnancy, irrespective of the sex of the child conceived.
The test is limited by current scientific knowledge regarding the gene and disease.
SANGER Analytical sensitivity >99.99%; Analytical specificity 99.99%.
MLPA Analytical sensitivity >99.99%; Analytical specificity 99.99%.
Clinical sensitivity: high variable expressivity has been reported in
Clinical specificity: data not available.
The genetic test is appropriate when:
the patient meets the diagnostic criteria for MFS;
the sensitivity of the test is greater than or equal to that of tests described in the literature.
| Clinical management | Utility |
|---|---|
| Confirmation of clinical diagnosis | Yes |
| Differential diagnosis | Yes |
| Couple risk assessment | Yes |
| Availability of clinical trials can be checked on-line at | |