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Test ID: KCNN4 KCNN4 Full Gene Sequencing, Varies

Necessary Information

The following information is required on patient information or test request form:

1. Clinical diagnosis

2. Pertinent clinical history (submit CBC results and relevant clinical notes)

3. Differentials based on clinical or morphologic presentation

4. Date of collection

5. Specimen type, whole blood or extracted DNA

Specimen Required

Submit only 1 of the following specimens:



Specimen Type: Peripheral blood


Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Green top (heparin)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

3. Label specimen as blood.

Specimen Stability Information: Ambient 14 days (preferred) or Refrigerated ≤30 days



Specimen Type: Extracted DNA from whole blood

Container/Tube: 1.5- to 2-mL tube with indication of volume and concentration of DNA

Specimen Volume: Entire specimen

Collection Instructions: Label specimen as extracted DNA from blood and provide indication of volume and concentration of the DNA

Specimen Stability Information: Frozen/Refrigerate/Ambient ≤30 days


1. Metabolic Hematology Next-Generation Sequencing (NGS) Patient Information is required, see Special Instructions.

2. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

Useful For

Genetic confirmation of a dehydrated hereditary stomatocytosis (DHSt) 2/hereditary xerocytosis diagnosis with the identification of an alteration known or suspected to cause disease in the KCNN4 gene


Second-tier testing for patients in whom previous targeted gene variant analyses were negative for a specific RBC membrane disorder


Establishing a diagnosis of a hereditary RBC membrane disorder, allowing for appropriate management and surveillance of disease features based on the gene involved, especially if splenectomy is a consideration

Method Name

Polymerase Chain Reaction (PCR) Amplification /Sanger Sequence Analysis

Reporting Name

KCNN4 Full Gene Sequencing, V

Specimen Type


Specimen Minimum Volume

Blood: 1 mL
Extracted DNA: 50 mcL at 50 ng/mcL concentration

Specimen Stability Information

Specimen Type Temperature Time Special Container
Varies Varies

Clinical Information

Dehydrated hereditary stomatocytosis (DHSt) 2 (also called hereditary xerocytosis) is an autosomal dominant hereditary hemolytic disorder caused by an abnormal cation leak in the red cell membrane, resulting in loss of a potassium cation and red blood cell dehydration. Pseudohyperkalemia (loss of red cell potassium when cold or at room temperature) can be a feature. Symptoms include compensated to mild hemolytic anemia, moderate splenomegaly, elevated reticulocyte count, increased mean corpuscular volume (MCV), variably increased mean corpuscular hemoglobin concentration (MCHC), perinatal edema, and a tendency for iron overload. Red cells exhibit various shape abnormalities on blood smear, including elliptocytes, schizocytes, and rare stomatocytes.


The majority of symptomatic DHSt cases reported to date have been associated with gain-of-function alterations in the mechanosensitive cation channel gene, PIEZO1. However, recent studies have identified families with DHSt associated with variants in the KCNN4 gene.(1-4) KCNN4 encodes for the Gardos channel, the erythroid voltage-independent potassium channel that is activated by intracellular calcium.(4) Pathogenic alterations in KCNN4 result in decreased intracellular total cation and potassium levels. Cases reported have shown abnormal ektacytometry curves typical of hereditary xerocytosis. Clinical features of KCNN4 patients include hemolytic anemia of variable severity that can be more severe in the perinatal period. Splenectomy may have no efficacy in symptom improvement in the few cases with KCNN4 variants.(2, 5)


This test is best interpreted in the context of protein studies and peripheral blood findings. This can be provided by also ordering RBCME / Red Blood Cell Membrane Evaluation, Blood. Please fill out the information sheet and indicate that KCNN4 testing was ordered. Providing CBC data and clinical notes will also allow more precise interpretation of results.

Reference Values

An interpretive report will be provided.


Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline.(3) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.


Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Clinical Reference

1. Glogowska E, Lezon-Geyda K, Maksimova Y, et al: Mutations in the Gardos channel (KCNN4) are associated with hereditary xerocytosis. Blood. 2015 Sep 10;126(11):1281-1284. doi: 10.1182/blood-2015-07-657957

2. Andolfo I, Russo R, Manna F, et al: Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis). Am J Hematol. 2015 Oct;90(10):921-926. doi: 10.1002/ajh.24117

3. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424. doi: 10.1038/gim.2015.30

4. Rapetti-Mauss R, Lacoste C, Picard V, et al: A mutation in the Gardos channel is associated with hereditary xerocytosis. Blood 2015 Sep;126(11):1273-1280. doi: 10.1182/blood-2015-04-642496

5. Iolascon A, Andolfo I, Barcellini W, et al: Working Study Group on Red Cells and Iron of the EHA. Recommendations regarding splenectomy in hereditary hemolytic anemias. Haematologica. 2017 Aug;102(8):1304-1313. doi: 10.3324/haematol.2016.161166

6. Andolfo I, Russo R, Rosato BE, et al: Genotype-phenotype correlation and risk stratification in a cohort of 123 hereditary stomatocytosis patients. Am J Hematol. 2018 Dec;93(12):1509-1517. doi: 10.1002/ajh.25276

7. Gallagher PG: Disorders of erythrocyte hydration. Blood. 2017 Dec 21;130(25):2699-2708. doi: 10.1182/blood-2017-04-590810

8. Fermo E, Bogdanova A, Petkova-Kirova P, et al: 'Gardos Channelopathy': a variant of hereditary Stomatocytosis with complex molecular regulation. Sci Rep. 2017 May 11;7(1):1744. doi: 10.1038/s41598-017-01591-w

Day(s) and Time(s) Performed

Monday through Friday; Varies

Analytic Time

8 weeks

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information


LOINC Code Information

Test ID Test Order Name Order LOINC Value
KCNN4 KCNN4 Full Gene Sequencing, V In Process


Result ID Test Result Name Result LOINC Value
607810 Interpretation 82939-0
607811 Signing Pathologist 19139-5
Mayo Clinic Laboratories | Hematology Catalog Additional Information: