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  • Test code: 06177
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae Pompe Disease Test

Test description

The Invitae Pompe Disease test analyzes the GAA gene, which is the only known gene to cause Pompe disease (also called glycogen storage disease, type II [GSD II]).

This test is intended for any individual, child or adult, who has an abnormal newborn screen for Pompe; a suspected clinical diagnosis of Pompe that is based on the clinical findings of significant hypotonia, cardiomegaly, and hepatomegaly in early infancy; or progressive muscle weakness (especially in a limb-girdle pattern) and respiratory difficulties. Further, any individual with prior low acid alpha-glucosidase (GAA) enzyme activity must undergo molecular analysis for Pompe. GAA has a known pseudodeficiency allele and, in Asian populations, homozygotes are present in up to 4% of individuals. Pseudodeficiency alleles result in 5%–20% of normal enzyme activity but do NOT cause clinical disease.

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Primary panel (1 gene)
Add-on Danon Disease Gene (1 gene)

There is significant clinical overlap between Pompe disease and Danon disease, and differentiating between these disorders by clinical symptoms alone can be difficult, especially early in the patient’s life. If clinically appropriate, this gene can be added at no additional charge.

LAMP2

Add-on Primary Carnitine Deficiency Gene (1 gene)

Primary carnitine deficiency can present from infancy through adulthood. Affected individuals tend to have muscle weakness in the extremities, shoulders, and hips. The heart muscle may also be weak and in children can become significantly enlarged. Depending on the patient’s clinical presentation, including this gene may be appropriate. This gene can be added for no additional charge.

SLC22A5

  • Pompe disease – also known as glycogen storage disease, type II (GSD II)
    • adult-onset Pompe disease
    • infantile-onset Pompe disease
    • juvenile-onset Pompe disease

Pompe disease is a glycogen-storage disease that leads to progressive deterioration of skeletal, heart, and smooth muscles. It is caused by a deficiency of the lysosomal enzyme acid-alpha glucosidase, which is involved in the catabolism of glycogen to glucose. The resulting accumulation of lysosomal glycogen leads to cellular dysfunction and organ damage.

Pompe disease demonstrates a phenotypic spectrum with varying degrees of myopathy, but two primary presentations are generally recognized: infantile and late-onset (often called adult-onset). These classifications are based on the age of symptom onset, extent of organ involvement, and rate of progression, and they are generally determined by the amount of underlying residual enzyme activity. In general, absent or minimal activity leads to severe, early-onset disease, and greater amounts cause a later-onset attenuated disease, but exceptions have been reported.

Infantile-onset Pompe is a multisystemic disorder and presents between eight and twelve weeks of age with significant hypotonia, weakness, cardiomyopathy, and hepatomegaly. Affected babies have difficulty feeding, fail to thrive, and are very “floppy,” with significant head lag. Massive cardiomegaly with cardiomyopathy leading to arrhythmias and cardiac failure is also evident. Respiratory function is also compromised, most infants require ventilatory support by six months of age. Untreated individuals usually die by one year of age due to cardiac or respiratory failure. Residual GAA activity is generally <1% of normal.

The late-onset (juvenile or adult) form can present anytime from late infancy onward and does not have the rapidly progressing disease that is observed in infantile cases. Adult cases are the most commonly recognized, and they present with nonspecific findings that overlap with other myopathies. The most prominent symptoms are progressive, debilitating muscle weakness, typically in a limb-girdle pattern, and respiratory problems. In some cases, respiratory problems may be the initial manifestation. Patients presenting after one year of age usually do not have cardiac hypertrophy, but arrhythmias have been described. Residual GAA activity is generally 2%–40% of normal.

Treatment for both infantile and late-onset forms of Pompe disease is available by enzyme replacement therapy.

Pompe disease is inherited in an autosomal recessive pattern.

The combined incidence of both adult and infantile forms of Pompe disease has been estimated at 1:40,000. Observed incidence varies between populations and geographic areas:

  • 1:14,000 African Americans
  • 1:138,000 Netherlands, infantile onset
  • 1:57,000 Netherland, adult onset
  • 1:35,000 Taiwan/South China
  • 1:600,000 Portugal

This test is intended for any individual, child or adult, who has an abnormal newborn screen for Pompe disease; suspected clinical diagnosis of Pompe that is based on the clinical findings of significant hypotonia, cardiomegaly, and hepatomegaly in early infancy; or progressive muscle weakness (especially in a limb-girdle pattern) and respiratory difficulties. Further, any individual with prior low acid alpha-glucosidase (GAA) enzyme activity must undergo variant analysis for Pompe. GAA has a known pseudodeficiency allele and, in Asian populations, homozygotes are present in up to 4% of individuals. Pseudodeficiency alleles result in 5%–20% normal enzyme activity but do NOT cause clinical disease.

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
GAA* NM_000152.3
LAMP2 NM_002294.2
SLC22A5 NM_003060.3

GAA: Analysis includes the promoter variant NM_000152.3:c.-32-13T>G as well as the common exon 18 deletion.