Test Id : RBART

The genes associated with Gitelman syndrome (SLC12A3) and autosomal dominant familial hypocalciuric hypercalcemia (FHH) (CASR) are not included on this panel. If testing for these disorders and Bartter syndrome on a single panel is desired, order RSCGP / Nephrocalcinosis, Nephrolithiasis, and Renal Electrolyte Imbalance Gene Panel, Varies. It is inappropriate to order both this test and RSCGP on the same patient because the genes on this panel are included on the RSCGP panel.

Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.

Customization of this panel and single gene analysis for any gene present on this panel are available. For more information, see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies.

Specimen preferred to arrive within 96 hours of collection.

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

Container/Tube:

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

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in original tube. Do not aliquot.

Specimen Stability Information: Ambient (preferred)/Refrigerated

• Informed Consent for Genetic Testing
• Informed Consent for Genetic Testing (Spanish)
• Hereditary Renal Genetic Testing Patient Information
• Targeted Genes and Methodology Details for Bartter Syndrome Gene Panel

1. 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)

2. Hereditary Renal Genetic Testing Patient Information (T918)

3. If not ordering electronically, complete, print, and send a Renal Diagnostics Test Request (T830) with the specimen.

1 mL

Providing a genetic evaluation for patients with a personal or family history suggestive of Bartter syndrome

Establishing a diagnosis of Bartter syndrome

This test utilizes next-generation sequencing to detect single nucleotide, deletion-insertion, and copy number variants in 6 genes associated with Bartter syndrome: BSND, CLCNKA, CLCNKB, KCNJ1, MAGED2, and SLC12A1. See Targeted Genes and Methodology Details for Bartter Syndrome Gene Panel in Method Description for additional details.

Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, familial screening, and genetic counseling for Bartter syndrome.

Bartter syndrome (BS) is a rare, hereditary tubulopathy of highly variable severity that can cause renal salt-wasting in infants and young children due to impaired sodium/chloride reabsorption in the thick ascending limb of the nephron.(1)

Characteristic clinical features are hypokalemic, hypochloremic metabolic alkalosis and normal blood pressure despite hyperreninemia and hyperaldosteronism.(1) Children with BS have hypercalciuria and normal serum magnesium levels and may present with symptoms in early childhood or before birth. These symptoms distinguish BS from a more common and milder renal salt-wasting disorder called Gitelman syndrome, which features hypocalciuria and low serum magnesium levels and typically presents after 6 years of age. Autosomal dominant hypocalcemia may resemble Bartter syndrome in patients with a markedly activating gain-of-function variant but is distinguishable from BS by mode of inheritance and the presence of hypocalcemia and hypomagnesemia.

Age of onset and disease severity is highly variable in Bartter syndrome. The most severe form, antenatal Bartter syndrome (also known as hyperprostaglandin E syndrome or neonatal Bartter syndrome), typically results in polyhydramnios, leading to premature birth. Infants often demonstrate failure to thrive and have significant polyuria resulting in risk for life-threatening salt and water loss.

There are four subtypes of Bartter syndrome that typically present antenatally. BS type 1, caused by biallelic alterations in SLC12A1, may also feature fever, vomiting, and nephrocalcinosis in infancy. BS type 2, caused by biallelic variants in KCNJ1, causes symptoms like BS type 1, but patients may demonstrate transient hyperkalemia and acidosis. BS type 4a, caused by biallelic alterations in BSND, and BS type 4b, caused by alterations in CLCNKA and CLCNKB, may be accompanied by sensorineural deafness in addition to renal salt-wasting and related symptoms. Type 4b is also inherited in an autosomal recessive (or biallelic) pattern or can result from digenic inheritance.

Classic Bartter syndrome, also known as type 3, is the second major form of BS and is caused by alterations in CLCNKB. All BS type 3 patients have marked hypochloremia. Age of onset varies in BS type 3 and may correlate with genotype, with individuals with truncating variants presenting earlier in life. Individuals with BS type 3 may present antenatally with polyhydramnios, during infancy with failure to thrive and lethargy, or in adolescence or adulthood with symptoms of chronic hypokalemia, such as constipation, muscle cramps, salt-craving, nocturia, and vomiting. Nephrocalcinosis is uncommon in BS type 3, and patients are usually normocalciuric but may still have severe electrolyte imbalances.

A third from of BS called transient neonatal Bartter syndrome (BS type 5), is associated with severe polyhydramnios and extreme salt wasting at birth that spontaneously resolves in the first few months of life in surviving patients. BS type 5 is caused by variants in MAGED2 inherited in an X-linked recessive pattern.

Although there is some phenotypic overlap between Bartter syndrome, Gitelman syndrome, and autosomal dominant hypocalcemia, they have different genetic causes.

This panel does not include the genes associated with Gitelman syndrome (SLC12A3) or autosomal dominant hypocalcemia (CASR). If simultaneous genetic testing for Bartter syndrome, Gitelman syndrome and/or autosomal dominant hypocalcemic hypercalciuria is desired, order RSCGP / Nephrocalcinosis, Nephrolithiasis, and Renal Electrolyte Imbalance Gene Panel, Varies.

An interpretive report will be provided.

All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(2) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Clinical Correlations:

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

If testing was performed because of a clinically significant family history, it is often useful to first test an affected family member. Detection of a reportable variant in an affected family member would allow for more informative testing of at-risk individuals.

To discuss the availability of additional testing options or for assistance in the interpretation of these results, contact the Mayo Clinic Laboratories genetic counselors at 800-533-1710.

Technical Limitations:

Next-generation sequencing may not detect all types of genomic variants. In rare cases, false-negative or false-positive results may occur. The depth of coverage may be variable for some target regions; assay performance below the minimum acceptable criteria or for failed regions will be noted. Given these limitations, negative results do not rule out the diagnosis of a genetic disorder. If a specific clinical disorder is suspected, evaluation by alternative methods can be considered.

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. Confirmation of select reportable variants will be performed by alternate methodologies based on internal laboratory criteria.

This test is validated to detect 95% of deletions up to 75 base pairs (bp) and insertions up to 47 bp. Deletions-insertions (delins) of 40 or more bp, including mobile element insertions, may be less reliably detected than smaller delins.

Deletion/Duplication Analysis:

This analysis targets single and multi-exon deletions/duplications; however, in some instances single exon resolution cannot be achieved due to isolated reduction in sequence coverage or inherent genomic complexity. Balanced structural rearrangements (such as translocations and inversions) may not be detected.

This test is not designed to detect low levels of mosaicism or to differentiate between somatic and germline variants. If there is a possibility that any detected variant is somatic, additional testing may be necessary to clarify the significance of results.

Genes may be added or removed based on updated clinical relevance. Refer to the Targeted Genes and Methodology Details for Bartter Syndrome Gene Panel for the most up to date list of genes included in this test. For detailed information regarding gene specific performance and technical limitations, see Method Description or contact a laboratory genetic counselor.

If the patient has had an allogeneic hematopoietic stem cell transplant or a recent blood transfusion, results may be inaccurate due to the presence of donor DNA. Call Mayo Clinic Laboratories for instructions for testing patients who have received a bone marrow transplant.

Reclassification of Variants:

At this time, it is not standard practice for the laboratory to systematically review previously classified variants on a regular basis. The laboratory encourages healthcare providers to contact the laboratory at any time to learn how the classification of a particular variant may have changed over time.

Variant Evaluation:

Evaluation and categorization of variants are performed using published American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations as a guideline.(2) Other gene-specific guidelines may also be considered. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Variants classified as benign or likely benign are not reported.

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 periodic updates to these tools may cause predictions to change over time. Results from in silico evaluation tools are interpreted with caution and professional clinical judgement.

Rarely, incidental findings or secondary findings may implicate another predisposition or presence of active disease. Incidental findings may include, but are not limited to, results related to the sex chromosomes. These findings will be carefully reviewed to determine whether they will be reported.

1. Fulchiero R, Seo-Mayer P. Bartter Syndrome and Gitelman Syndrome. Pediatr Clin North Am. 2019 Feb;66(1):121-134.

2. 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.

Capture-based and amplicon-based next-generation sequencing (NGS) and/or Sanger sequencing is performed to test for the presence of variants in coding regions and intron/exon boundaries of the genes analyzed, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletions-insertions (delins) less than 40 base pairs (bp), above 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction (PCR)-based quantitative method is performed to test for the presence of deletions and duplications in the genes analyzed.

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. See the Targeted Genes and Methodology Details for Bartter Syndrome Gene Panel for details regarding the targeted genes analyzed for each test and specific gene regions not routinely covered.(Unpublished Mayo method)

Confirmation of select reportable variants may be performed by alternate methodologies based on internal laboratory criteria.

Genes analyzed: BSND, CLCNKA, CLCNKB, KCNJ1, MAGED2, SLC12A1

Varies

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

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81479 (if appropriate for government payers)