The Invitae GM2 gangliosidosis Test analyzes 3 genes associated with the GM2-gangliosidoses. Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants provide accurate risk assessment and determine carrier status in at-risk relatives.
Additionally, any individual with low β hexosaminidase enzyme activity must undergo variant analysis. The genes encoding the alpha and beta subunits of β hexosaminidase have known pseudodeficiency alleles which can lead to a false positive result on enzyme analysis. Pseudodeficiency alleles do NOT cause clinical disease.
GM2A HEXA HEXB
GM2A HEXA HEXB
For a broader analysis of the genetics of lysosomal disorders:
The GM2 gangliosidoses are a group of clinically indistinguishable neurodegenerative lysosomal storage diseases due to excessive accumulation of GM2 ganglioside. GM2 gangliosides are components of plasma membranes and are most abundant in neurons. Inability to degrade GM2 gangliosides results in progressive accumulation within the lysosome and eventual neuronal dysfunction.
The enzyme β hexosaminidase has two forms that are involved in GM2 ganglioside degradation: β hexosaminidase A and β hexosaminidase B. β hexosaminidase A is composed of an alpha and a beta subunit, while β hexosaminidase B is composed of two beta subunits. HEXA encodes the alpha subunit and is affected in Tay Sachs disease. HEXB encodes the beta subunit and affects both enzymes β hexosaminidase A and β hexosaminidase B leading to Sandhoff disease. The GM2 activator protein is not an enzyme, but extracts GM2 from the plasma membrane and presents it for degradation; it is encoded by GM2A.
All three GM2 gangliosidoses have similar phenotypes that are clinically indistinguishable. They manifest as a spectrum with severe early infantile presentations to attenuated adult-onset forms. The infantile forms are the most commonly recognized with onset typically between three and six months of age. Affected infants present with progressive muscle weakness, difficulty coordinating muscle movement, decreased attentiveness, and an increased startle response. These symptoms progress to seizures, loss of developmental milestones, blindness and deafness. A characteristic cherry-red spot is seen on ophthalmologic examination. Additionally, organomegaly may also be observed. Death typically occurs by four years of age.
Later onset juvenile and adult cases are less common, present with variable neurologic findings, and less severe disease progression. Symptoms in older individuals may include ataxia, cognitive impairment, and mental illness; cherry-red spots may not be present. Lifespan for older affected individuals may not be affected.
Approximately 99% of individuals with Tay-Sachs disease have two identifiable pathogenic variants in the HEXA gene.
For patients with a clinical and biochemical diagnosis of Sandhoff disease, approximately 96% will have two pathogenic variants detected in HEXB (PMID: 22848519).
All of the GM2 gangliosidoses follow autosomal recessive inheritance.
Tay Sachs disease
Prevalence is specific to various sub-populations. Carrier frequency is 1 in 27 in the Ashkenazi Jewish, French Canadian, Pennsylvania Amish, and Louisiana Cajun populations. This corresponds to a disease frequency of approximately 1 in 3,600. In the Irish American population, the carrier frequency is 1 in 50. In the general population, excluding these sub-populations, the carrier frequency is approximately 1 in 250, corresponding to a disease incidence of approximately 1 in 320,000 individuals.
Incidence 1 in 300,000 in the general population. Several population isolates in northern Argentina, Saskatchewan, and Cyprus have been identified with higher prevalence
GM2 AB variant is exceedingly rare, but may be underdiagnosed.
Genetic testing can be a useful tool to decipher the cause of reduced β hexosaminidase activity. Reduced enzymatic activity can be due to a pseudodeficiency allele or a disease-causing variant gene. Approximately 35% of non-Jewish individuals identified as carriers through enzyme analysis are actually pseudodeficiency carriers and not carriers of Tay-Sachs disease.
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|