1. DISEASE CHARACTERISTICS
1.1 Name of the disease (synonyms)
Gitelman syndrome, Gitelman's syndrome, familial hypokalemia-hypomagnesemia.
1.2 OMIM# of the disease
1.3 Name of the analysed genes or DNA/chromosome segments
1.4 OMIM# of the gene(s)
1.5 Mutational spectrum
There are more than 140 different mutations in SLC12A3.1, 2, 4, 8, 9, 11, 14, 15, 16 These mutations include missense-, nonsense-, frame-shift-, and splice-site mutations. In addition, deletions of (part) the gene have been identified.
Only a few mutations in CLCNKB have been identified; patients with CLCNKB mutations have a highly variable phenotype, ranging from an antenatal onset of Bartter syndrome on one side of the spectrum, to a phenotype closely resembling Gitelman syndrome at the other side. Therefore, there is an indication to screen the CLCNKB gene in patients with the Gitelman phenotype who do not have mutations in the SLC12A3 gene.
1.6 Analytical methods
Direct automated sequencing for mutations.
MLPA for deletions.
1.7 Analytical validation
Internal validation through analysis of known mutations in anonymized samples.
1.8 Estimated frequency of the disease (incidence at birth (‘birth prevalence’) or population prevalence)
1 in 40 000.
1.9 If applicable, prevalence in the ethnic group of investigated person
1.10 Diagnostic setting
Comment: a prenatal test is technically feasible, but as yet has never been asked for because of the good prognosis in the majority of patients.
2. TEST CHARACTERISTICS
2.1 Analytical sensitivity (proportion of positive tests if the genotype is present)
For both genes nearly 100% for the coding regions and splice sites.
2.2 Analytical specificity (proportion of negative tests if the genotype is not present)
100% for both 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 a quantification can only be made case by case.
80% for SLC12A3, but in 30% only one mutant SLC12A3 allele is detected.
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 a quantification can only be made case by case.
2.5 Positive clinical predictive value (life time risk to develop the disease if the test is positive)
100%, but the symptoms may be very mild and the disease may only be detected during biological check-up, including measurement of serum Mg2+ and urinary Ca2+.
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:
If both SLC12A3 and CLCNKB are excluded in this non-affected person the negative predictive value is >90%.
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?
3.1.2 Describe the burden of alternative diagnostic methods to the patient?
The tests are primarily blood and urine tests. So, the only burden is the drawing of a blood sample, which is also necessary for the genetic test.
3.1.3 How is the cost effectiveness of alternative diagnostic methods to be judged?
Genetic testing is at the moment more expensive than biochemistry, but this may change in future.
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):
If the test result is negative (please describe):
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)?
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?
Not applicable. See also comment at 1.10.
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, for the confirmation of the diagnosis and for genetic counselling.
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OD and NK were supported by EUNEFRON, an FP7 project of the European Community (GA# 201590). 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).
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Knoers, N., Devuyst, O. & Kamsteeg, EJ. Clinical utility gene card for: Gitelman syndrome. Eur J Hum Genet 19, 1–3 (2011). https://doi.org/10.1038/ejhg.2011.14
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