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Test Catalog

Test ID: NGHHA    
Hereditary Hemolytic Anemia Comprehensive Panel, Next-Generation Sequencing, Varies

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

Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of hereditary hemolytic anemias, including RBC membrane/hydration disorders, RBC enzymopathies and congenital dyserythropoietic anemia

 

Comprehensive testing for patients in whom previous targeted gene mutation analyses were negative for a specific hereditary hemolytic anemia

 

Establishing a diagnosis of a hereditary hemolytic anemia or related disorder, allowing for appropriate management and surveillance of disease features based on the gene involved, especially if splenectomy is a consideration (2)

 

Identifying mutations within genes associated with phenotypic severity, allowing for predictive testing and further genetic counseling

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

See Targeted Genes Interrogated by NGHHA Next-Generation Sequencing in Special Instructions for a list of the genes and exons targeted by this test.

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

See NGHHA and Subpanel Comparison Gene List in Special Instructions.

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

Next-generation sequencing (NGS) is a methodology that can interrogate large regions of genomic DNA in a single assay. The presence and pattern of gene mutations can provide critical diagnostic, prognostic, and therapeutic information for managing physicians.

 

This test is best interpreted in the context of protein studies and peripheral blood findings. This can be provided by ordering the HAEVP / Hemolytic Anemia Evaluation Profile test. Please fill out the information sheet and indicate that NGS testing was also ordered. Providing CBC data and clinical notes will also allow more precise interpretation of results.

 

Hereditary hemolytic anemias are caused by defects in one or more of the genes that control RBC production, metabolism, or structure, resulting in faulty erythropoiesis, cell membranes, or enzymes required for normal RBC function. 

 

This panel aids in the diagnosis and treatment for hereditary (congenital) hemolytic anemia.(1,2) The panel includes genes known to cause hereditary anemia including those implicated in RBC enzyme,(3) RBC membrane/RBC hydration,(4) and congenital dyserythropoietic anemia(5) disorders. This panel can aid in the differential diagnosis of early onset and lifelong myopathic or neurologic syndromes, especially if associated with hemolysis. Specifically, this panel assays genes associated with hereditary spherocytosis (HS), hereditary elliptocytosis (HE), hereditary pyropoikilocytosis (HPP), Southeast Asian ovalocytosis, hereditary stomatocytosis (both overhydrated and dehydrated/hereditary xerocytosis subtypes), and cryohydrocytosis. Hereditary stomatocytosis is a RBC membrane permeability disorder that can manifest as the more common dehydrated hereditary stomatocytosis (DHSt), also known as hereditary xerocytosis (HX) and the rarer overhydrated hereditary stomatocytosis (OHSt) subtypes. These disorders are important to confirm or exclude as splenectomy has been associated with an increased risk for serious venous thrombosis and thromboembolism events and is contraindicated in published guidelines.(7) It also includes genes associated with RBC enzymopathies, ranging from the common glucose 6 phosphate dehydrogenase (G6PD) and pyruvate kinase (PK) deficiencies, to the rarer disorders of adenylate kinase (AK1), hexokinase (HK1), phosphofructokinase (PFKM), phosphoglycerate kinase (PGK1), pyruvate kinase (PKLR), glutathione pathway, and triosephosphate isomerase (TPI1).

 

This panel also includes multiple genes associated with congenital dyserythropoietic anemia (CDA), types 1a, 1b, 2, 3, and 4. CDA is a disorder of ineffective erythropoiesis associated with distinctive bone marrow morphologic changes. A limited number of the most common genes associated with Fanconi anemia (FA) and Diamond-Blackfan anemia (DBA) are also analyzed by this panel; however, this panel is not intended as a thorough investigation of FA or DBA.

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 recommendations as a guideline.(6,7) 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 mutation that is not identified by the methods performed. The absence of a mutation, 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.

 

Technical:

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. Nathan and Oski's Hematology of Infancy and Childhood. Edited by SH Orkin, DG Nathan, D Ginsburg, et al. Seventh edition. Philadelphia, Saunders Elsevier, 2009, pp 455-1108

2. Iolascon A, Andolfo I, Barcellini W, et al: Recommendations for splenectomy in hereditary hemolytic anemias. Haematologica 2017 May 26. PMID: 28550188. doi: 10.3324/haematol.2016.161166.

3. Koralkova P, van Solinge WW, van Wijk R: Rare hereditary red blood cell enzymopathies associated with hemolytic anemia - pathophysiology, clinical aspects, and laboratory diagnosis. Int J Lab Hematol 2014 Jun;36(3):388-397

4. King MJ, Garçon L, Hoyer JD, et al: International Council for Standardization in Haematology. ICSH guidelines for the laboratory diagnosis of nonimmune hereditary red cell membrane disorders. Int J Lab Hematol 2015 Jun;37(3):304-325

5 Gambale A, Iolascon A, Andolfo I, Russo R: Diagnosis and management of congenital dyserythropoietic anemias. Expert Rev Hematol 2016 Mar;9(3):283-296

6. 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;17:405-424

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