Is there a genetic test for hereditary hypokalemia?

Genetic Testing for Hereditary Hypokalemia

Yes, genetic testing is available and recommended for hereditary hypokalemia, particularly when clinical features suggest Bartter syndrome, Gitelman syndrome, or related tubulopathies.

When to Order Genetic Testing

Genetic testing should be pursued in patients presenting with:

• Unexplained hypokalemia with metabolic alkalosis, especially when accompanied by normal or low blood pressure 1, 2
• Hypocalciuria and hypomagnesemia, which strongly suggest Gitelman syndrome 3, 4
• Hypercalciuria with or without nephrocalcinosis, pointing toward Bartter syndrome types I or II 5, 2
• Salt-wasting tubulopathy with polyuria and volume depletion despite ongoing urinary losses 2
• Family history of similar electrolyte abnormalities or consanguinity 6, 7
• Hypertension with unexplained hypokalemia where secondary causes have been excluded, as BS/GS can paradoxically present with elevated blood pressure 7

Recommended Gene Panel

The minimum genetic testing panel should include 2, 3:

• SLC12A3 (Gitelman syndrome - most common cause)
• SLC12A1 (Bartter syndrome type I)
• KCNJ1 (Bartter syndrome type II)
• CLCNKB (Bartter syndrome type III)
• BSND (Bartter syndrome type IV)

Extended panel should additionally cover 3:

• CLCNKA, KCNJ10, FXYD2, HNF1B (Gitelman-like syndromes)
• MT-TI, MT-TF (mitochondrial causes)
• KCNJ16, ATP1A1 (novel causes of Na+-wasting tubulopathy)

The diagnostic yield is approximately 2.94-17.65% in patients with unexplained hypertension and hypokalemia, and significantly higher when classic phenotypic features are present 7.

Critical Diagnostic Workup Before Genetic Testing

Laboratory assessment to guide gene selection 2:

• Urinary calcium-creatinine ratio: Hypocalciuria (<0.2) suggests Gitelman syndrome; hypercalciuria suggests Bartter syndrome types I or II 2, 4
• Serum magnesium: Hypomagnesemia strongly favors Gitelman syndrome 5, 3
• Fractional excretion of chloride: Typically >0.5% in salt-wasting tubulopathies 2
• Renal ultrasound: Nephrocalcinosis indicates Bartter syndrome types I or II 2
• Renin and aldosterone levels: Hyperreninemic hyperaldosteronism expected 2

Functional testing can help localize the tubular defect 4:

• Furosemide challenge tests Henle's loop function (abnormal in Bartter syndrome)
• Thiazide challenge tests distal convoluted tubule function (abnormal in Gitelman syndrome)

Genetic Testing Methodology

Next-generation sequencing (NGS) is the preferred approach 5, 3:

• DNA from peripheral blood is recommended for germline variant detection 5
• Deletion/duplication testing is mandatory, as large deletions represent 11-19% of pathogenic variants in SDHB, SDHC, and SDHD genes, and up to 30% in related genes 5
• Analytical sensitivity is 90-100% in children when appropriate gene panels are used 2

Variant Interpretation and Confirmation

When a variant is identified 5:

• Pathogenic or likely pathogenic variants that fit the clinical phenotype warrant cascade testing of family members
• Variants of unknown significance require segregation analysis in affected relatives to establish pathogenicity 5
• Functional studies may be needed in research settings for novel variants 5

For Bartter syndrome specifically, immunohistochemistry can support pathogenicity, though this applies more to SDHx-related conditions 5.

Special Considerations

Gitelman syndrome inheritance patterns 6:

• Typically autosomal recessive, but compound heterozygotes are common
• Rare cases show inheritance across multiple generations when both parents carry mutations
• Genetic testing is essential for precise evaluation of complicated family pedigrees 6

Bartter syndrome Type 1 (HNF1B-related) 5:

• May present with hypokalemia and hypomagnesemia
• Often has extrarenal manifestations including MODY5 diabetes, renal cysts, and genital abnormalities
• Not all HNF1B-related disease should be classified as tubulointerstitial kidney disease 5

Common Pitfalls to Avoid

• Do not limit testing to SLC12A3 alone - the genetic spectrum has expanded significantly to include mitochondrial and novel nuclear genes 3
• Do not overlook deletion/duplication analysis - point mutation sequencing alone misses a substantial proportion of pathogenic variants 5
• Do not assume normal blood pressure excludes these diagnoses - up to 17.65% of patients with hypertension and hypokalemia may have BS/GS 7
• Do not use potassium citrate for supplementation while awaiting genetic results, as non-chloride potassium salts worsen metabolic alkalosis 2
• Do not delay genetic testing in patients with suggestive phenotypes, as it guides long-term management and enables family screening 2, 7