Article Category: Technical Report
Pubblicato online: 19 set 2018
Pagine: 38 - 41
DOI: https://doi.org/10.2478/ebtj-2018-0033
Parole chiave
© 2018 Yeltay Rakhmanov, Paolo Enrico Maltese, Stefano Paolacci, 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: Loeys-Dietz syndromes, arterial tortuosity syndrome, thoracic aortic aneurysms and dissections, thoracic aortic aneurysms and dissections associated with bicuspid aortic valve, aortic aneurysms with cutis laxa)
Marfan-like disorders are inherited conditions with features resembling Marfan syndrome but that do not match all the diagnostic criteria of the Revised Ghent Nosology (2010) and/or that do not share a pathogenic variant in
The prevalence of Marfan-like disorders is unknown.
To establish a clinical diagnosis or suspicion, the following multiple diagnostic procedures should be used: clinical examination and history, heart ultrasound, eye examination with slit lamp for lens dislocation, advanced imaging studies of the vascular tree.
Differential diagnosis should consider Marfan syndrome, congenital contractural arachnodactyly/Beals syndrome, homocystinuria caused by cystathionine β-synthase deficiency, Stickler syndrome and fragile X syndrome.
Marfan-like disorders have different phenotypes and clinical features. Inheritance is usually autosomal dominant; cutis laxa, Ehlers-Danlos syndromes and moyamoya disease may show autosomal recessive or dominant transmission patterns (2, 3, 4, 5, 6, 7, 8, 9, 10, 11).
MASS syndrome (OMIM disease 604308) -
Shprintzen-Goldberg craniosynostosis syndrome (SGS, OMIM disease 182212) -
Loeys-Dietz syndrome 1 (LDS1, OMIM disease 609192) -
Loeys-Dietz syndrome 2 (LDS2, OMIM disease 610168) -
Loeys-Dietz syndrome 3 (LDS3, OMIM disease 613795) -
Loeys-Dietz syndrome 4 (LDS4, OMIM disease 614816) -
Loeys-Dietz syndrome 5 (LDS5, OMIM disease 615582) -
Familial thoracic aortic aneurysm 4 (AAT4, OMIM disease 132900) -
Familial thoracic aortic aneurysm 6 (AAT6, OMIM disease 611788) -
Familial thoracic aortic aneurysm 7 (AAT7, OMIM disease 613780) -
Familial thoracic aortic aneurysm 8 (AAT8, OMIM disease 615436) -
Familial thoracic aortic aneurysm 9 (AAT9, OMIM disease 616166) -
Familial thoracic aortic aneurysm 10 (AAT10, OMIM disease 617168) -
Cutis laxa autosomal dominant 1 (ADCL1, OMIM disease 123700) -
Cutis laxa autosomal dominant 2 (ADCL2, OMIM disease 614434) -
Cutis laxa autosomal dominant 3 (ADCL3, OMIM disease 616603) -
Aortic valve disease 1 (AOVD1, OMIM disease 109730) -
Aortic valve disease 2 (AOVD 2, OMIM disease 614823) -
Moyamoya disease 5 (MYMY5, OMIM disease 614042) –
Ehlers-Danlos syndrome, classic type 1 (EDSCL1, OMIM disease 130000) –
Ehlers-Danlos syndrome, classic type 2 (EDSCL2, OMIM disease 130010) -
Ehlers-Danlos syndrome, periodontal type 1 (EDSPD1, OMIM disease 130080) -
Ehlers-Danlos syndrome, periodontal type 2 (EDSPD2, OMIM disease 617174) -
Ehlers-Danlos syndrome, arthrochalasia type (EDSARTH, OMIM disease 130060) -
Ehlers-Danlos syndrome, vascular type (EDSVASC, OMIM disease 130050) -
Arterial tortuosity syndrome (ATS, OMIM disease 208050) -
Autosomal recessive cutis laxa type 1A (ARCL1A, OMIM disease 219100) -
Autosomal recessive cutis laxa type 1B (ARCL1B, OMIM disease 614437) -
Autosomal recessive cutis laxa type 2A (ARCL2A, OMIM disease 219200) -
Autosomal recessive cutis laxa type 3A (ARCL3A, OMIM disease 219150) -
Moyamoya disease 6 with achalasia (MYMY6, OMIM disease 615750) -
Ehlers-Danlos syndrome, dermatosparaxis type (EDSDERMS, OMIM disease 225410) -
Ehlers-Danlos syndrome, kyphoscoliotic type 1 (OMIM disease 225400) –
Ehlers-Danlos syndrome, kyphoscoliotic type 2 (EDSKSCL2, OMIM disease 614557) -
Ehlers-Danlos syndrome, spondylodysplastic type 1 (EDSSPD1, OMIM disease 130070) -
Ehlers-Danlos syndrome, spondylodysplastic type 2 (EDSSPD2, OMIM disease 615349) -
Ehlers-Danlos syndrome, spondylodysplastic type 3 (EDSSPD3, OMIM disease 612350) -
Ehlers-Danlos syndrome, cardiac valvular type (EDSCV, OMIM disease 225320) -
Ehlers-Danlos syndrome, musculocontractural type 1 (EDSMC1, OMIM disease 601776) – (
Ehlers-Danlos syndrome, musculocontractural type 2 (EDSMC2, OMIM disease 615539) -
Ehlers-Danlos syndrome, classic-like (EDSCLL, OMIM disease 606408) -
Pathogenic variants may include missense, nonsense, splicing, small insertions and deletions, small indels, gross insertions, duplications.
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 47 accredited medical genetic laboratories in the EU, and in the GTR database, offered by 14 accredited medical genetic laboratories in the US.
Guidelines for clinical use of the test are described in Genetics Home Reference (
A multi-gene next generation sequencing panel is used for the detection of nucleotide variations in coding exons and flanking introns of the above genes. Potentially causative variants and regions with low coverage are Sanger-sequenced. Sanger sequencing is also used for family segregation studies.
Multiplex Ligation Probe Amplification (MLPA) is used to detect duplications and deletions in
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 pathogenic variants in the above genes confirms the clinical diagnosis and is an indication for family studies.
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.
If the identified pathogenic variant has autosomal dominant transmission, the probability that an affected carrier transmit the disease variant to his/her children is 50% in any pregnancy, irrespective of the sex of the child conceived.
In autosomal recessive mutations, both parents are usually healthy carriers. In this case, the probability of transmitting the disorder to the offspring is 25% in any pregnancy of the couple, irrespective of the sex of the child. An affected individual generates healthy carrier sons and daughters in all cases, except in pregnancies with a healthy carrier partner. In these cases, the risk of an affected son or daughter is 50%.
The test is limited by current scientific knowledge regarding the gene and disease.
NGS Analytical sensitivity >99.99%, with a minimum coverage of 10X; Analytical specificity 99.99%.
SANGER Analytical sensitivity >99.99%; Analytical specificity 99.99%.
MLPA Analytical sensitivity >99.99%; Analytical specificity 99.99%.
Clinical sensitivity: variations in the aforementioned genes are linked to Marfan-like syndromes, but may be individual variations (identified in one or a few families) and total epidemiological data is therefore not available.
Clinical specificity: data not available.
The genetic test is appropriate when:
the patient meets the diagnostic criteria for a Marfan-like syndrome;
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 | |