Clinical utility gene card for: Prototypic hereditary recurrent fever syndromes (monogenic autoinflammatory syndromes)

Subjects

1. Disease characteristics

1.1 Name of the diseases (synonyms)

1.6 Analytical methods

The method of choice for all genes is sequencing exons and intronic boundaries. Because the most frequent clearly pathogenic mutations cluster in specific exons (MEFV: exon 10; TNFRSF1A: exons 2–3–4; and NLRP3: exon 3), it is not necessary in routine procedure to analyze all exons for each gene. See EMQN guidelines.1

1.7 Analytical validation

External quality assessment (EQA) may be performed regularly, for example, in Europe by EMQN schemes.

1.8 Estimated frequency of the diseases (Incidence at birth (‘birth prevalence’) or population prevalence)

1.9 Diagnostic setting

Comment:

Depending on countries and age of individuals predictive testing and risk assessment is allowed and performed or not. Prenatal diagnosis may be discussed in some cases of CINCA (CAPS).

2. Test characteristics

2.1 Analytical sensitivity

(proportion of positive tests if the genotype is present)

Depending on the quality of sequencing almost 100% for MEFV−, MVK−, TNFRSF1A−, NLRP3−, and NLRP12− genes

2.2 Analytical specificity

(proportion of negative tests if the genotype is not present)

Depending on quality of sequencing almost 100% for MEFV−, MVK−, TNFRSF1A−, NLRP3−, and NLRP12− genes

2.3 Clinical sensitivity

(proportion of positive tests if the disease is present)

The clinical sensitivity can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if quantification can only be made case by case.

There are many causes for recurrent fever attacks; hence, it is difficult to define a clinical sensitivity. In cases where two mutations are identified, for example, the MEFV gene, it is presumed, because of high analytical sensitivity, that the patient has FMF.

2.4 Clinical specificity

(proportion of negative tests if the disease is not present)

The clinical specificity can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if quantification can only be made case by case.

There are many causes for recurrent fever attacks; hence, it is difficult to define a clinical specificity. In cases where no mutation is identified, for example, in the MEFV gene, it is presumed, because of high analytical specificity, that the patient has not FMF due to mutations in the MEFV gene, but it does not exclude a clinical diagnosis of FMF, and hence a corresponding treatment has not to be excluded.

2.5 Positive clinical predictive value (life time risk to develop the disease if the test is positive)

All these monogenic autoinflammatory syndromes (FMF, MKD, TRAPS, CAPS, and FCAS2) are children’s diseases, hence adult onset is unusual. However, the FMF patients carrying the homozygous p.Met694Val genotype have obviously higher life time risk to develop amyloidosis.8

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.

There are many causes for recurrent fever attacks; hence it is difficult to define a negative clinical predictive value. For example, in cases where no mutation is identified in the MEFV gene, it is presumed, because of high analytical specificity, that the patient does not have FMF at least due to mutations in the MEFV gene, but it does not exclude a clinical diagnosis of FMF from criteria described by Livneh et al.2

3. Clinical utility

3.1 (Differential) diagnostics: the tested person is clinically affected

(To be answered if in 1.9 ‘A’ was marked)

3.1.1 Can a diagnosis be made other than through a genetic test?

3.1.2 Describe the burden of alternative diagnostic methods to the patient

Delay in diagnostic resulting in life threatening complications (all diseases);

Multiple surgery unnecessary explorations (especially in FMF and maybe in TRAPS)

3.1.3 How is the cost effectiveness of alternative diagnostic methods to be judged?

Not applicable

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 1.9 ‘B’ was marked)

It is better not to test unaffected individuals. In cases with risk of amyloidosis it may be useful to know the genotype.

3.2.1 Will the result of a genetic test influence lifestyle and prevention?

If the test result is positive (please describe)

If necessary symptoms have to be treated and kidneys have to be observed.

If the test result is negative (please describe)

Genetic testing was done because of symptoms hence despite negative test result the patient will be treated as necessary.

3.2.2 Which options in view of lifestyle and prevention does a person at-risk have if no genetic test has been done (please describe)?

Not applicable because the patient has symptoms and in any case that will be treated as possible.

3.3 Genetic risk assessment in family members of a diseased person

(To be answered if in 1.9 ‘C’ was marked)

3.3.1 Does the result of a genetic test resolve the genetic situation in that family?

It may sometimes resolve the genetic situation in a family.

3.3.2 Can a genetic test in the index patient save genetic or other tests in family members?

Yes, genetic testing saves genetic or other testing in family members.

3.3.3 Does a positive genetic test result in the index patient enable a predictive test in a family member?

Yes, it may partly enable predictive testing in family members.

3.4 Prenatal diagnosis

(To be answered if in 1.9 ‘D’ was marked)

3.4.1 Does a positive genetic test result in the index patient enable a prenatal diagnosis?

Yes, by knowing the mutations prenatal diagnosis will be possible, but only in some cases of CINCA (CAPS) prenatal diagnosis may be discussed.

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)

References

  1. 1

    Shinar Y, Obici L, Aksentijevich I et al: Guidelines for the genetic diagnosis of hereditary recurrent fevers. Ann Rheum Dis 2012; 71: 1599–1605.

    CAS  Article  Google Scholar 

  2. 2

    Livneh A, Langevitz P, Zemer D et al: Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 1997; 40: 1879–1885.

    CAS  Article  Google Scholar 

  3. 3

    Kotter I, Schedel J, Kummerle-Deschner JB : [Periodic fever syndrome/autoinflammatory syndrome]. Z Rheumatol 2009; 68: 137–148, quiz 149.

    CAS  Article  Google Scholar 

  4. 4

    Jeru I, Duquesnoy P, Fernandes-Alnemri T et al: Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci USA 2008; 105: 1614–1619.

    CAS  Article  Google Scholar 

  5. 5

    Solak M, Yildiz H, Koken R et al: Analysis of familial Mediterranean fever gene mutations in 202 patients with familial Mediterranean fever. Genet Test 2008; 12: 341–344.

    CAS  Article  Google Scholar 

  6. 6

    Lainka E, Neudorf U, Lohse P et al: Analysis of cryopyrin-associated periodic syndromes (CAPS) in German children: epidemiological, clinical and genetic characteristics. Klin Padiatr 2010; 222: 356–361.

    CAS  Article  Google Scholar 

  7. 7

    Cuisset L, Jeru I, Dumont B et al: Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis 2011; 70: 495–499.

    CAS  Article  Google Scholar 

  8. 8

    Dusunsel R, Dursun I, Gunduz Z, Poyrazoglu MH, Gurgoze MK, Dundar M : Genotype-phenotype correlation in children with familial Mediterranean fever in a Turkish population. Pediatr Int 2008; 50: 208–212.

    CAS  Article  Google Scholar 

  9. 9

    Jeru I, Hentgen V, Normand S et al: Role of interleukin-1beta in NLRP12-associated autoinflammatory disorders and resistance to anti-interleukin-1 therapy. Arthritis Rheum 2011; 63: 2142–2148.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by EuroGentest2 (Unit 2: ‘Genetic testing as part of health care’), a Coordination Action under FP7 (Grant Agreement Number 261469), and the European Society of Human Genetics.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Martina Witsch-Baumgartner.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Witsch-Baumgartner, M., Touitou, I. Clinical utility gene card for: Prototypic hereditary recurrent fever syndromes (monogenic autoinflammatory syndromes). Eur J Hum Genet 23, 1111 (2015). https://doi.org/10.1038/ejhg.2014.257

Download citation

Further reading

Search

Quick links