1. DISEASE CHARACTERISTICS
1.1 Name of the disease (synonyms)
Ehlers–Danlos syndrome types I/II, III, IV, VI, VIIA/B, and VIIC; or according to the Villefranche nosology: classical type (EDS I and II), hypermobile type (EDS III), vascular type (EDS IV), kyphoscoliotic type (EDS VI), arthrochalasic types (EDS VIIA and EDS VIIB), dermatosparactic type (EDS VIIC), unspecified types, and varia.1, 2
1.2 OMIM# of the disease
130000, 130010, 130020, 130050, 225400, 130060, 225410, and 612350.
1.3 Name of the analysed genes or DNA/chromosome segments
COL5A1, COL5A2, TNXB, COL3A1, PLOD1, ZNF469, COL1A1, COL1A2, ADAMTS2, and SLC39A13.
1.4 OMIM# of the gene(s)
120215, 120190, 600985, 120180, 153454, 229200, 120150, 120160, 604539, and 608735.
1.5 Mutational spectrum
Missense mutations, nonsense mutations, splice mutations, insertions, deletions, genomic rearrangements.
Presently, more than 270 mutations are known for all 10 genes together. The majority of them (about 170) are in the COL3A1 gene.
1.6 Analytical methods
Genomic sequencing of coding regions, eventually multiple ligation-dependent analysis (MLPA) for detection of genomic rearrangements and large deletions.
1.7 Analytical validation
Direct sequencing of both DNA strands; verification of sequence and MLPA results with second DNA extraction or second PCR or hybridisation (MLPA).
1.8 Estimated frequency of the disease (incidence at birth (‘birth prevalence’) or population prevalence)
1.9 If applicable, prevalence in the ethnic group of investigated person
Not applicable for most EDS types except for EDS type VIA which is most prevalent in the Middle East.
1.10 Diagnostic setting
Prenatal diagnosis is rarely requested for Ehlers–Danlos syndrome.
2. TEST CHARACTERISTICS
2.1 Analytical sensitivity (proportion of positive tests if the genotype is present)
Nearly 100%, if a deletion/duplication diagnostic test has been made for genes with the possibility of a rearrangement.
2.2 Analytical specificity (proportion of negative tests if the genotype is not present)
2.3 Clinical sensitivity (proportion of positive tests if the disease is present)
The clinical sensitivity can be dependant on variable factors such as age or family history. In such cases a general statement should be given, even if only a quantification can be made case by case.
It is 50% for EDS type I/II (COL5A1 and COL5A2 genes) which is genetically heterogeneous with additional, still unknown gene loci.
It is 95% for EDS type IV (COL3A1 gene), EDS types VIIA and VIIB (COL1A1 and COL1A genes, respectively) as well as EDS type VIA (PLOD1 gene).
Not known in EDS type VIB (ZNF469 gene) and EDS type VIIC (ADAMTS2 gene).
2.4 Clinical specificity (proportion of negative tests if the disease is not present)
The clinical specificity can be dependant on variable factors such as age or family history. In such cases a general statement should be given, even if only a quantification can be made case by case.
2.5 Positive clinical predictive value (lifetime risk to develop the disease if the test is positive)
100% penetrance with, depending on EDS type, variable clinical expressivity.
2.6 Negative clinical predictive value (probability not to develop the disease if the test is negative)
Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered.
Index case in that family had been tested:
Index case in that family had not been tested:
5%–95%, corresponding to the detection rate in the genes of the different EDS types. This question arises quite often in EDS type IV if the index patient has died already.
3. CLINICAL UTILITY
3.1 (Differential) diagnosis: the tested person is clinically affected
(To be answered if in 1.10 ‘A’ was marked)
3.1.1 Can a diagnosis be made other than through a genetic test?
Because EDS comprises a group of different entities, each with higly variable clinical expressivity, a primary molecular genetic analysis for differential diagnostics is indicated in only exceptional cases with classical clinical features and known associated mutations. Histological/ultrastructural and biochemical/biophysical investigations should be performed initially, if ever possible. The significance of different collagen diagnostic approaches in different EDS types is illustrated in the table.
3.1.2 Describe the burden of alternative diagnostic methods to the patient
Initial clinical, biochemical, and ultrastructural investigations complement the molecular genetic analysis that, however, cannot replace the former.
3.1.3 How is the cost effectiveness of alternative diagnostic methods to be judged?
3.1.4 Will disease management be influenced by the result of a genetic test?
3.2 Predictive setting: the tested person is clinically unaffected but carries an increased risk based on family history
(To be answered if in 1.10 ‘B’ was marked)
3.2.1 Will the result of a genetic test influence lifestyle and prevention?
If the test result is positive (please describe):
Frequent interdisciplinary follow-up, depending on EDS type.
Specific therapeutic support of joints and musculature. Avoidance of sports with physical contacts in EDS types with predominant involvement of joints.
Scrutiny for eventually developing aneurysms, special caution during surgery, tight follow-up of pregnancy, emergency card in EDS types with vascular involvement. Wound protection in EDS types with involvement of skin and a tendency to haematomas.
If the test result is negative (please describe):
Follow-up dispensable, if a familial mutation can be excluded.
3.2.2 Which option in view of lifestyle and prevention does a person at risk have if no genetic test has been done (please describe)?
Interdisciplinary follow-up considering all possible EDS types if the index patient had not been analysed genetically.
Regular and specific follow-up if the index patient's EDS type is known.
3.3 Genetic risk assessment in family members of a diseased person
(To be answered if in 1.10 ‘C’ was marked)
3.3.1 Does the result of a genetic test resolve the genetic situation in that family?
3.3.2 Can a genetic test in the index patient save genetic or other tests in family members?
3.3.3 Does a positive genetic test result in the index patient enable a predictive test in a family member?
3.4 Prenatal diagnosis
(To be answered if in 1.10 ‘D’ was marked)
3.4.1 Does a positive genetic test result in the index patient enable a prenatal diagnostic?
4. IF APPLICABLE, FURTHER CONSEQUENCES OF TESTING
Please assume that the result of a genetic test has no immediate medical consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (please describe)
Yes. In many cases, the genetic diagnostics contribute substantially to classifaction of EDS type if clinical, biochemical, and ultrastructural findings are not fully informative. Recognising clinical symptoms as belonging to the Ehlers–Danlos syndrome and classifying them as a given EDS type is prerequisite for clinical prognosis, specific therapy, and official acceptance as severe handicap. In children with a tendency to haematomas, a suspicion of child abuse may be alleviated through the correct diagnosis of EDS type. The correct diagnosis will end a diagnostic odyssey and the unwarranted suspicion of hypochondria, and the appropriate patient organisation can now be approached.
Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ : Ehlers–Danlos syndromes: revised nosology, Villefranche, 1997. Am J Med Genet 1998; 77: 31–37.
Steinmann B, Royce PM, Superti-Furga A : The Ehlers–Danlos syndrome; in Royce PM, Steinmann B (eds): Connective Tissue and its Heritable Disorders, 2nd edn, New York: Wiley-Liss, 2002, pp 431–523.
This work was supported by EuroGentest, an EU-FP6-supported NoE, contract number 512148 (EuroGentest Unit 3: ‘Clinical genetics, community genetics and public health’, Workpackage 3.2).
The authors declare no conflict of interest.