Glycogen Storage Disorders Panel, Sequencing

Glycogen storage diseases (GSDs) are a group of inborn errors of metabolism, typically caused by enzyme defects, resulting in a buildup of glycogen in the liver, muscles, and other organs. Specific clinical presentation and age of onset depends on the particular type of GSD; there are many types and subtypes, and other disorders may have overlapping phenotypes.

Disease Overview

Common clinical features of these disorders include:

• Hepatomegaly
• Poor growth or short stature
• Hypoglycemia (marked by fatigue, irritability, headaches, pallor)
• Muscle weakness and/or pain
• Cardiomyopathy
• Exercise intolerance
• Liver disease (cirrhosis)

Testing Strategy

Depending on the type of GSD suspected, consideration may be given to laboratory workup that may include the following tests:

• Serum creatine kinase
• Blood glucose (fasting/nonfasting)
• Cholesterol
• Liver enzymes (eg, alanine transaminase [ALT] and aspartate transaminase [AST])
• Triglycerides
• Uric acid
• Urine organic acids
• Plasma acylcarnitines
• Blood lactate
• Imaging studies (magnetic resonance imaging [MRI] or ultrasound)
• Tissue biopsy

Genetics

Etiology

Pathogenic germline variants in genes associated with GSDs or related disorders (see Genes Tested table)

Inheritance

Primarily autosomal recessive (AR); rarely autosomal dominant (AD) or X-linked (XL)

Penetrance

Variable, depending on the specific type of GSD

Test Interpretation

Clinical Sensitivity

Variable, depending on the specific type of GSD

Analytic Sensitivity:

For massively parallel sequencing:

Results

Limitations

• A negative result does not exclude a diagnosis of a GSD.
• Diagnostic errors can occur due to rare sequence variations.
• Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
• The following will not be evaluated:
  • Variants outside the coding regions and intron-exon boundaries of targeted gene(s)
  • Regulatory region and deep intronic variants, including GBE1 (NM_000158.4) intron 15
    • Includes an Ashkenazi Jewish founder mutation in GBE1 (HGMD ID: CX153579)
  • Noncoding transcripts
  • The following exons are not sequenced due to technical limitations of the assay:
    • ENO3 (NM_001374524) exon(s) 1
    • OXCT1 (NM_001364299) exon(s) 5
    • OXCT1 (NM_001364300) exon(s) 1
    • OXCT1 (NM_001364303) exon(s) 1
    • PFKM (NM_001354735) exon(s) 4
    • PFKM (NM_001354736) exon(s) 4
    • PFKM (NM_001354740) exon(s) 1
    • PFKM (NM_001354741) exon(s) 2
  • Large deletions/duplications in any of the tested genes
• The following may not be detected:
  • Deletions/duplications/insertions of any size by massively parallel sequencing
  • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
  • Low-level somatic variants

Genes Tested