Glycogen Storage Disorders - Muscle Panel: Sequencing and CNV Analysis

Glycogen storage disorders (GSDs) are a group of inherited genetic defects of glycogen metabolism. Most of them have autosomal recessive inheritance, however there are a few exceptions. There are more than 20 subtypes classified by the specific enzyme deficiency, affected tissue, and disease phenotype. Clinical and biochemical features continue to be used reliably to assign patients to this general disease category. Identification of the precise genetic defect is important, as molecular analysis is likely to expand the clinical spectrum of GSDs, may provide data relevant to prognosis and future therapeutic intervention and is important for carrier testing and early prenatal diagnosis.

The overall incidence of GSDs as a group is estimated to be 1 in 20,000-43,000 births. GSDs primarily affect the liver, the muscle, or both. Although the phenotype range is broad, the majority of clinical manifestations are hepatomegaly, failure to thrive, hypoglycemia, hyperlactatemia, hyperuricemia, and hyperlipidemia. This GSD panel covers 15 genes in which pathogenic variants cause the muscle isoforms of GSD and disorders that have overlapping phenotype with GSDs.

References:

• Burwinkel et al. (2005), Am J Hum Genet, 76:1034-1049.

• Morris et al. (1995), J Inherit Metab Dis, 18:28-32.

• Santer, Steinmamm, and Schaub. (2002), Curr Mol Med, 2:213-227.

AGL, ENO3, GAA, GBE1, GYS1, LAMP2, PFKM, PGAM2, PGM1, PHKB, PRKAG2, PYGM

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This test is indicated for:

• Confirmation of a clinical diagnosis of glycogen storage disorders (GSDs).

• Carrier testing in adults with a family history of glycogen storage disorders (GSDs).

Next Generation Sequencing: In-solution hybridization of all coding exons is performed on the patient's genomic DNA. Although some deep intronic regions may also be analyzed, this assay is not meant to interrogate most promoter regions, deep intronic regions, or other regulatory elements, and does not detect single or multi-exon deletions or duplications. Direct sequencing of the captured regions is performed using next generation sequencing. The patient's gene sequences are then compared to a standard reference sequence. Potentially causative variants and areas of low coverage are Sanger-sequenced. Sequence variations are classified as pathogenic, likely pathogenic, benign, likely benign, or variants of unknown significance. Variants of unknown significance may require further studies of the patient and/or family members.

Copy Number Analysis: Comparative analysis of the NGS read depth (coverage) of the targeted regions of genes on this panel was performed to detect copy number variants (CNV). The accuracy of the detected variants is highly dependent on the size of the event, the sequence context and the coverage obtained for the targeted region. Due to these variables and limitations a minimum validated CNV size cannot be determined; however, single exon deletions and duplications are expected to be below the detection limit of this analysis.

• Pompe (dry blood spot - test code DZ; leukocytes - DW).
• Glycogen Storage Disorders- Muscle: Deletion/Duplication Panel

Requisition Forms

• Exome Test Requisition Form
• Metabolic/Newborn Screening Follow-up Test Requisition Form

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