Genetic Testing

Genetic testing is the primary means for diagnosis of MFM13. Single-gene testing is recommended in the case of a known familial HSPB8 variant while multi-gene panel sequencing in undifferentiated cases.

Currently, HSPB8 is not included in myopathy panels in the USA. It is included in Distal Myopathy NHS panel in the UK.

HSPB8 gene can be added to diagnostic panels such as congenital myopathy panel, comprehensive myopathy panel, distal myopathy panel comprehensive Neuromuscular disorders panel, etc. by request of the ordering physician.

Providers using Invitae for genetic testing can build custom panels to include HSPB8. For details, please contact Invitae’s Client Services division, either through main phone line (1-800-436-3037) or email (clientservices@invitae.com)

Whole Exome Sequencing (WES) or Whole Genome Sequencing (WGS) can be ordered; however, the results may or may not reveal the variant. Correlation with clinical presentation, family history, other lab findings, and genetic counselling is highly recommended. Providers ordering WES and other genetic testing should include clinical notes and all required documentation to facilitate insurance coverage.

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The identification of a pathogenic HSPB8 variant confirms the diagnosis in a clinically affected individual. The identification of a likely pathogenic variant may be considered diagnostic; however, further evidence would be required for reclassification of the variant.

A variant of unknown significance (VUS) is a change in HSPB8 that has not previously been associated with human disease; insufficient data exists to support whether the variant is benign or pathogenic, and therefore such a result needs further analysis as a possible new pathogenic variant before being considered as not clinically actionable. Once a diagnosis is confirmed, carrier testing is recommended for other family members. 

Detailed information regarding genetic variant interpretation and pathogenicity criteria may be found by referring to American College of Medical Genetics criteria

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Where to test?

* Providers using Invitae for genetic testing can build custom panels to include HSPB8. For details, please contact Invitae’s Client Services division, either through main phone line (1-800-436-3037) or email (clientservices@invitae.com)

1) NIH Genetic Testing Registry - The Genetic Testing Registry (GTR®) provides a central location for voluntary submission of genetic test information by providers. The scope includes the test's purpose, methodology, validity, evidence of the test's usefulness, and laboratory contacts and credentials. The overarching goal of the GTR is to advance the public health and research into the genetic basis of health and disease

2) Genomics England Panel App - HSPB8 gene is included in the ‘Distal Myopathies’ Panel

A crowdsourcing tool to allow gene panels to be shared, downloaded, viewed and evaluated by the Scientific Community.

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3) Genetic Testing Locations and Providers - Below is a list of laboratories that offer genetic testing for HSPB8, either as single gene analysis or as part of broader neuromuscular or myopathy panels. This resource is intended to support clinicians and families seeking diagnostic options for suspected HSPB8-related Myofibrillar Myopathy type 13 (MFM13) with Rimmed Vacuoles [OMIM #621078].

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Other testing:

• Blood tests: Elevated Creatine Kinase (CK). Some patients may have dyslipidemia and elevated liver enzymes.

• Electrocardiography: Some patients might present with cardiomyopathy and conduction defects such as right bundle branch block.

• Echocardiogram may show left ventricular hypertrophy and reduced ejection fraction.

• Pulmonary function studies could be normal or might show respiratory insufficiency, restrictive lung disease with decreased Forced Vital Capacity (FVC)

• Nerve conduction studies (NCS) showing axonal motor neuropathy predominantly affecting the lower limbs.

• Electromyography (EMG) findings with features of mixed myopathic and neurogenic pathology in the upper and lower limbs.

• MRI (or CT scan) of the lower limbs with fatty degenerative changes in the proximal and distal lower extremities - Figures B and C

• Muscle biopsy can be done if there is diagnostic uncertainty and/or no genetic mutation is identified in genes associated with myopathies. Patients with mutations in HSPB8 gene develop myopathy displaying histologic features of myofibrillar myopathy like the pathology in myopathies due to gene defects in other components of the CASA complex such as BAG3 and DNAJB6. Muscle biopsy typically shows fatty replacement, aggregates, rimmed vacuoles, increased internalized nuclei, and endomysial fibrosis.

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