Test Catalog

Test ID: KCNN4    
KCNN4 Full Gene Sequencing, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

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

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test detects pathogenic alterations within the KCNN4 gene which are associated with hereditary stomatocytosis.


The gene target for this test includes the following:

Gene name (transcript): KCNN4 (GRCh37 (hg19) NM_002250)

Chromosomal location: chr19q13.31

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

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 Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

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.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances


Some individuals may have a sequence variant that is not identified by the methods performed. The absence of a variation, therefore, does not eliminate the possibility of hereditary hemolytic anemia or a related disorder. This assay does not distinguish between germline and somatic alterations, particularly with variant allele frequencies (VAF) significantly lower than 50%. Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete. 


If there is a family history of hereditary hemolytic anemia or a related disorder, it is often useful to test first-degree family members to help establish the clinical significance of variants of unknown significance.


At this time, it is not standard practice for the laboratory to systematically review likely pathogenic variants or variants of uncertain significance that have been previously detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.



Some genetic or genomic alterations, such as large insertion/deletion (indel) events, copy number alterations, and gene translocation events are not detected by this assay. The depth of coverage may be variable for some target regions, but assay performance below the minimum acceptable criteria or for failed regions will be noted. Additionally, rare polymorphisms may be present that could lead to false-negative or false-positive results. If results do not match clinical findings, consider alternative methods for analyzing these genes, such as Sanger sequencing or large deletion and duplication analysis. If the patient has had an allogenic blood transfusion, these results may be inaccurate due to the presence of donor DNA.

Clinical Reference Recommendations for in-depth reading of a clinical nature

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

Special Instructions Library of PDFs including pertinent information and forms related to the test