Clinical utility gene card for: Gitelman syndrome

1. DISEASE CHARACTERISTICS

1.1 Name of the disease (synonyms)

Gitelman syndrome, Gitelman's syndrome, familial hypokalemia-hypomagnesemia.

1.2 OMIM# of the disease

263800.

1.3 Name of the analysed genes or DNA/chromosome segments

SLC12A3, CLCNKB.

1.4 OMIM# of the gene(s)

600968, 602023.

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

Not applicable.

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.

100%.

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:

 100%.

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):

Not applicable.

If the test result is negative (please describe):

Not applicable.

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.

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?

Not applicable.

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

Not applicable.

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

Not applicable.

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.

References

  1. 1

    Simon DB, Nelson-Williams C, Bia MJ et al: Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 1996; 12: 24–30.

    CAS  Article  Google Scholar 

  2. 2

    Lemmink HH, Knoers NV, Károlyi L et al: Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. Kidney Int 1998; 54: 720–730.

    CAS  Article  Google Scholar 

  3. 3

    Ring T, Knoers N, Oh MS, Halperin ML : Reevaluation of the criteria for the clinical diagnosis of Gitelman syndrome. Pediatr Nephrol 2002; 17: 612–616.

    Article  Google Scholar 

  4. 4

    Reissinger A, Ludwig M, Utsch B et al: Novel NCCT gene mutations as a cause of Gitelman's syndrome and a systematic review of mutant and polymorphic NCCT alleles. Kidney Blood Press Res 2002; 25: 354–362.

    Article  Google Scholar 

  5. 5

    Knoers NVAM, Starremans PGJF, Monnens LAH : Hypokalaemic tubular disorders; in Daviesion AM, Cameron JS, Grunfeld J-P, Ponticelli C. Ritz E, Winearls CG, van Ypersele C (eds): Oxford Textbook of Clinical Nephrology. 3rd edn. Oxford: Oxford University Press, 2005, pp 955–1004.

    Google Scholar 

  6. 6

    Knoers NV : Gitelman syndrome. Adv Chronic Kidney Dis 2006; 13: 148–154.

    Article  Google Scholar 

  7. 7

    Riveira-Munoz E, Chang Q, Bindels RJ, Devuyst O : Gitelman syndrome: towards genotype-phenotype correlations? Pediatr Nephrol 2007; 22: 326–332.

    Article  Google Scholar 

  8. 8

    Bouwer ST, Coto E, Santos F, Angelicheva D, Chandler D, Kalaydjieva L : The Gitelman syndrome mutation, IVS9+1G>T, is common across Europe. Kidney Int 2007; 72: 898.

    CAS  Article  Google Scholar 

  9. 9

    Riveira-Munoz E, Chang Q, Godefroid N et al: Transcriptional and functional analyses of SLC12A3 mutations: New clues for the pathogenesis of Gitelman's syndrome. J Am Soc Nephrol 2007; 18: 1271–1283.

    CAS  Article  Google Scholar 

  10. 10

    Devuyst O : Salt wasting and blood pressure. Nat Genet 2008; 40: 495–496.

    CAS  Article  Google Scholar 

  11. 11

    Shao L, Liu L, Miao Z et al: A novel SLC12A3 splicing mutation skipping of two exons and preliminary screening for alternative splice variants in human kidney. Am J Nephrol 2008; 28: 900–907.

    CAS  Article  Google Scholar 

  12. 12

    Devuyst O, Konrad M, Jeunemaitre X : Tubular disorders of electrolyte regulation; in Avner ED, Harmon WE, Niaudet P, Yoshikawa N (eds): Pediatric Nephrology. 6th edn. New York: Springer, 2009, pp 929–978.

    Google Scholar 

  13. 13

    Knoers NV : Inherited forms of renal hypomagnesemia: an update. Pediatr Nephrol 2009; 24: 697–705.

    Article  Google Scholar 

  14. 14

    Nozu K, Iijima K, Nozu Y et al: A deep intronic mutation in the SLC12A3 gene leads to Gitelman syndrome. Pediatr Res 2009; 66: 590–593.

    CAS  Article  Google Scholar 

  15. 15

    Qin L, Shao L, Ren H et al: Identification of five novel variants in the thiazide-sensitive NaCl co-transporter gene in Chinese patients with Gitelman syndrome. Nephrology (Carlton) 2009; 14: 52–58.

    CAS  Article  Google Scholar 

  16. 16

    Hsu YJ, Yang SS, Chu NF, Sytwu HK, Cheng CJ, Lin SH : Heterozygous mutations of the sodium chloride cotransporter in Chinese children: prevalence and association with blood pressure. Nephrol Dial Transplant 2009; 24: 1170–1175.

    CAS  Article  Google Scholar 

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Acknowledgements

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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Correspondence to Nine VAM Knoers.

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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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