Test Code GNMY9 MYH9-Related Disorders, MYH9 Gene, Next-Generation Sequencing, Varies

Ordering Guidance

This test is designed to evaluate MYH9-related disorders, including May-Hegglin disorder/anomaly and Sebastian syndrome, and to be utilized for genetic confirmation of a phenotypic diagnosis of an MYH9-related disorder.

If testing for hereditary platelet disorders using a larger panel is desired, a 70-gene platelet disorder panel is available; order GNPLT / Platelet Disorders, Comprehensive Gene Panel, Next-Generation Sequencing, Varies.

This test is not designed to evaluate for hereditary bleeding disorders. For patients with clinical suspicion of an inherited bleeding disorder, it is important to exclude plasmatic factor deficiencies (eg, von Willebrand disease, hemophilia, or other factor deficiencies) prior to considering an inherited platelet function defect. If bleeding is the indication for testing and testing for hereditary bleeding disorders is desired, bleeding panels are available. For more information see GNBLF / Bleeding Disorders, Focused Gene Panel, Next-Generation Sequencing, Varies or GNBLC / Bleeding Disorders, Comprehensive Gene Panel, Next-Generation Sequencing, Varies.

For assessment of hereditary platelet disorders that have ultrastructural abnormalities, such as gray platelet syndrome, order PTEM / Platelet Transmission Electron Microscopic Study, Whole Blood.

For assessment of hereditary platelet disorders due to quantitative surface glycoprotein deficiencies, order PLAFL / Platelet Glycoprotein Flow Platelet Surface Glycoprotein by Flow Cytometry, Blood.

Testing for the MYH9 gene as part of a customized panel is available. For more information see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies.

Targeted testing for familial variants (also called site-specific or known variants testing) is available for the MYH9 gene. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.

Shipping Instructions

Specimen preferred to arrive within 96 hours of collection.

Necessary Information

Platelet Esoteric Testing Patient Information is required. Testing may proceed without the patient information, however, the information aids in providing a more thorough interpretation. Ordering providers are strongly encouraged to fill out the form and send with the specimen.

Specimen Required

Specimen Type: Whole blood

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)

Acceptable: Yellow top (ACD)

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) 4 days/Refrigerated

Forms

1. Platelet Esoteric Testing Patient Information 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 an Coagulation Test Request (T753) with the specimen.

Secondary ID

619299

Useful For

Evaluating MYH9-related disorders, including May-Hegglin disorder/anomaly and Sebastian syndrome, in patients with a personal or family history suggestive of an MYH9-related disorder

Diagnosing MYH9-related disorders, including May-Hegglin disorder/anomaly and Sebastian syndrome, for patients in whom phenotypic testing is nondiagnostic, but there is a strong clinical suspicion of the MYH9-related disorder

Confirming an MYH9-related disorder diagnosis with the identification of a known or suspected disease-causing alteration in the MYH9 gene

Determining the disease-causing alterations within the MYH9 gene to delineate the underlying molecular defect in a patient with a laboratory diagnosis of an MYH9-related disorder

Identifying the causative alteration for genetic counseling purposes

Prognosis and risk assessment based on the genotype-phenotype correlations

Providing a prognosis in syndromic MYH9-related disorders

Carrier testing for close family members of an individual with an MYH9-related disorder diagnosis

This test is not intended for prenatal diagnosis

Testing Algorithm

The clinical workup for detecting inherited platelet disorders should begin with a careful review of a patientâ€™s complete blood cell count and platelet indices results, peripheral blood smear, and other platelet tests, such as light transmission platelet aggregometry, electrical impedance whole blood aggregometry, and platelet function analyzer 100 (PFA-100). Platelet transmission electron microscopy is an essential tool for laboratory diagnosis of various hereditary platelet disorders, and platelet flow cytometric analysis is the preferred method to assess hereditary platelet disorders due to quantitative surface glycoprotein deficiencies

Due to the reduced sensitivity of functional testing, occasionally, the clinical picture may be consistent with a defect in primary hemostasis, but results of platelet tests may be normal or non-diagnostic.

Genetic testing for hereditary platelet disorders is indicated if:

-Platelet tests indicate a deficiency or functional abnormality, and abnormal platelet or white blood cell morphology by light or electron microscopy

-There is a clinical suspicion for a hereditary platelet disorder due to family history or patientâ€™s clinical presentation

-Acquired causes of deficiencies associated with platelet disorders have been excluded

If a platelet disorder is a concern, a set of clinical guidelines from the British Society for Haematology on testing for heritable platelet disorders is freely available.(1)

Special Instructions

Method Name

Sequence Capture and Targeted Next-Generation Sequencing (NGS) followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing.

Reporting Name

MYH9 Gene, Full Gene NGS

Specimen Type

Varies

Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type	Temperature	Time	Special Container
Varies	Varies

Reject Due To

All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.

Clinical Information

Platelets have essential roles in primary hemostasis. Patients with either hereditary or acquired platelet disorders usually have bleeding diathesis, which can potentially be life-threatening, and may also have issues with the development and/or functioning of major organs.(2) Inherited platelet disorders can be syndromic (ie, associated with current or future development of other organ system defects) or nonsyndromic (ie, isolated to thrombocytopenia with no other organ system defects).

A reliable laboratory diagnosis of a platelet disorder can significantly impact patients' and, potentially, their family members' clinical management and outcome. Identification of an alteration that is known or suspected to cause disease aids in confirmation of the diagnosis and, potentially, provides prognostic information especially in the syndromic inherited platelet disorders.

This test evaluates the MYH9 gene, which is associated with a variety of MYH9-related disorders, including May-Hegglin disorder/anomaly, Sebastian syndrome, Fechtner syndrome, Epstein syndrome, MYH9-related syndromic thrombocytopenia, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, and macrothrombocytopenia with leukocyte inclusions.

The risk for developing bleeding or other phenotypic features associated with these disorders and syndromes varies. The MYH9 gene has established bleeding, thrombocytopenia, and syndromic risk, and also expert group guidelines.(1,3-5)

It is recommended that genetic testing be offered to all patients suspected of having a heritable platelet disorder since some patients may have normal platelet laboratory testing results.(1,6) Genetic testing is integral to the conclusive diagnosis of an MYH9-related disorder.(5,6)

Reference Values

An interpretive report will be provided.

Interpretation

All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(8) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Method Description

Next-generation sequencing (NGS) and/or Sanger sequencing are performed to test for the presence of variants in coding regions and intron/exon boundaries of the MYH9 gene, 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 deletion-insertionsÂ 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-based quantitative method is performed to test for the presence of deletions and duplications in the MYH9 gene.

There may be regions of the MYH9 gene 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.(Unpublished Mayo method)

The reference transcript for MYH9 is NM_002473.5. Reference transcript numbers may be updated due to transcript re-versioning. Always refer to the final patient report for gene transcript information referenced at the time of testing. Confirmation of select reportable variants may be performed by alternate methodologies based on internal laboratory criteria.

Day(s) Performed