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-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 red blood cell (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

Highlights

Variants in KCNN4 are associated with a rare red blood cell membrane disorder, dehydrated hereditary stomatocytosis, which causes chronic hemolytic anemia.

 

Informative protein studies (eg, osmotic fragility, ektacytometry) and peripheral blood findings, correlated with the patient clinical history, should be performed prior to genetic testing.

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

Method Name
A short description of the method used to perform the test

Polymerase Chain Reaction (PCR) Amplification/Sanger Sequencing

NY State Available
Indicates the status of NY State approval and if the test is orderable for NY State clients.

Yes

Reporting Name
Lists a shorter or abbreviated version of the Published Name for a test

KCNN4 Full Gene Sequencing, V

Aliases
Lists additional common names for a test, as an aid in searching

DHS2

DHSt 2

Potassium calcium-activated channel subfamily N member 4

Specimen Type
Describes the specimen type validated for testing

Varies

Necessary Information

The following information is required on either the Metabolic Hematology Next-Generation Sequencing (NGS) Patient Information (T816) or test request form:

1. Clinical diagnosis

2. Pertinent clinical history (submit complete blood cell count 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
Defines the optimal specimen required to perform the test and the preferred volume to complete testing

Submit only 1 of the following specimens:

 

Preferred:

Specimen Type: Whole blood

Container/Tube:

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 whole blood specimen in original tube. Do not aliquot.

3. Label specimen as blood.

Specimen Stability Information: Ambient 14 days (preferred)/Refrigerated < or =30 days

 

Acceptable:

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 < or =30 days

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

Forms

1. Metabolic Hematology Next-Generation Sequencing (NGS) Patient Information (T816) is required.

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:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

3. If not ordering electronically, complete, print, and send a Benign Hematology Test Request (T755) with the specimen.

Specimen Minimum Volume
Defines the amount of sample necessary to provide a clinically relevant result as determined by the Testing Laboratory

Blood: 1 mL

Extracted DNA: 50 mcL at 50 ng/mcL concentration

Reject Due To
Identifies specimen types and conditions that may cause the specimen to be rejected

Gross hemolysis Reject
Gross lipemia OK
Bone marrow biopsies
Paraffin-embedded tissue
Frozen tissue
Slides
Paraffin-embedded bone marrow aspirate clot
Methanol-acetic acid fixed pellets
Moderately to severely clotted
Reject

Specimen Stability Information
Provides a description of the temperatures required to transport a specimen to the performing laboratory, alternate acceptable temperatures are also included

Specimen Type Temperature Time Special Container
Varies Varies

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

Genetic confirmation of a dehydrated hereditary stomatocytosis-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 red blood cell (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-2 (DHS2) (also called hereditary xerocytosis) is an autosomal dominant hereditary hemolytic disorder caused by an abnormal cation leak in the red blood cell membrane, resulting in loss of a potassium cation and red blood cell dehydration. Pseudohyperkalemia (loss of red blood 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 blood cells exhibit various shape abnormalities on blood smear, including elliptocytes, schizocytes, and rare stomatocytes.

 

The majority of symptomatic DHS 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 DHS 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) Disease-causing 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, which 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. Fill out the information sheet and indicate that KCNN4 testing was ordered. Providing complete blood cell count data and clinical notes will 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 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

Clinical:

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 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 a 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 disease-causing 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.

 

Technical:

Some genetic or genomic alterations, such as large deletion-insertion (delin) 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 variants (ie, 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

Method Description
Describes how the test is performed and provides a method-specific reference

Total genomic DNA is extracted from the sample, and the full KCNN4 gene is amplified by polymerase chain reaction followed by Sanger sequencing of the 5' and 3'UTR (untranslated regions) and exons 1-9, including 10 base pairs on each intron/exon boundary. Review of the sequence data is performed using a combination of automated calls and manual inspection.(Unpublished Mayo method)

PDF Report
Indicates whether the report includes an additional document with charts, images or other enriched information

No

Day(s) Performed
Outlines the days the test is performed. This field reflects the day that the sample must be in the testing laboratory to begin the testing process and includes any specimen preparation and processing time before the test is performed. Some tests are listed as continuously performed, which means that assays are performed multiple times during the day.

Monday through Friday

Report Available
The interval of time (receipt of sample at Mayo Clinic Laboratories to results available) taking into account standard setup days and weekends. The first day is the time that it typically takes for a result to be available. The last day is the time it might take, accounting for any necessary repeated testing.

8 to 10 weeks

Specimen Retention Time
Outlines the length of time after testing that a specimen is kept in the laboratory before it is discarded

Whole blood: 2 weeks; DNA: 3 months

Performing Laboratory Location
Indicates the location of the laboratory that performs the test

Rochester

Fees
Several factors determine the fee charged to perform a test. Contact your U.S. or International Regional Manager for information about establishing a fee schedule or to learn more about resources to optimize test selection.

  • Authorized users can sign in to Test Prices for detailed fee information.
  • Clients without access to Test Prices can contact Customer Service 24 hours a day, seven days a week.
  • Prospective clients should contact their Regional Manager. For assistance, contact Customer Service.

Test Classification
Provides information regarding the medical device classification for laboratory test kits and reagents. Tests may be classified as cleared or approved by the US Food and Drug Administration (FDA) and used per manufacturer instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR) product.

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 US Food and Drug Administration.

CPT Code Information
Provides guidance in determining the appropriate Current Procedural Terminology (CPT) code(s) information for each test or profile. The listed CPT codes reflect Mayo Clinic Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing.

CPT codes are provided by the performing laboratory.

81479

LOINC® Information
Provides guidance in determining the Logical Observation Identifiers Names and Codes (LOINC) values for the order and results codes of this test. LOINC values are provided by the performing laboratory.

Test Id Test Order Name Order LOINC Value
KCNN4 KCNN4 Full Gene Sequencing, V 98954-1
Result Id Test Result Name Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
607810 Interpretation 82939-0
607811 Signing Pathologist 19139-5

Test Setup Resources

Setup Files
Test setup information contains test file definition details to support order and result interfacing between Mayo Clinic Laboratories and your Laboratory Information System.

Excel | Pdf

Sample Reports
Normal and Abnormal sample reports are provided as references for report appearance.

Normal Reports | Abnormal Reports

SI Sample Reports
International System (SI) of Unit reports are provided for a limited number of tests. These reports are intended for international account use and are only available through MayoLINK accounts that have been defined to receive them.

SI Normal Reports | SI Abnormal Reports