Sandhoff Disease via the HEXB Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
476 HEXB$870.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
Pathogenic variants in the HEXB gene have been documented in the vast majority of patients with clinical features of GM2 gangliosidosis and deficiency of both beta-hexosaminidase A and B isoenzymes activities in plasma or cultured fibroblasts (Zampieri et al. 2009; Kaya et al. 2011; Aryan et al. 2012).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 HEXB$990.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity
Several large pathogenic deletions have been reported in the HEXB gene. One of these, a 16-kb deletion spanning the first five exons, accounts for about 27% of pathogenic HEXB variants in patients from various ethnic and geographic origins (Neote et al. 1990). This deletion represents about 50% of pathogenic variants in Iranian patients with Sandhoff disease (Aryan et al. 2012).

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Clinical Features
Sandhoff disease, also called GM2 Gangliosidosis Type II, is a neurodegenerative lysosomal storage disorder due to deficiency in both beta-hexosaminidase A and B isoenzymes. It is characterized by the accumulation of GM2 ganglioside, particularly in the brain, and by the storage of related glycolipids in the brain and in visceral organs (Sandhoff et al. 1971). Sandhoff disease is clinically heterogeneous. Three distinct clinical forms are recognized on the basis of age of onset of symptoms, clinical features, and disease progression (Kolter and Sandhoff 2006; Gravel et al. 2001).

1) Infantile Sandhoff disease, like Infantile Tay-Sachs disease, is characterized by onset before the age of 6 months, rapid progression and death by 4 years of age. Symptoms begin with a cherry-red spot in the macula, visual abnormalities, seizures, decline of physical and mental abilities and progress to blindness, deafness, paralysis and difficulty to swallowing. Unlike Tay-Sachs disease, organomegaly and slight bone deformation may occur in Sandhoff disease.

2) Juvenile Sandhoff disease is clinically heterogeneous. It is distinguished by onset of symptoms between 3-10 years of age. Clinical features include cerebellar ataxia, loss of movement coordination, progressive spasticity, dystonia, slow deterioration of speech, gait and posture, and cerebellar atrophy. Vision is spared. Death occurs in the early twenties.

3) Adult Sandhoff disease is also clinically heterogeneous. It is characterized by age of onset ranging from adolescence to adulthood, and slow progression. Symptoms include seizures, unsteady gait, cognitive loss, deterioration of speech, and psychosis.

The prevalence of Sandhoff disease has been estimated at 1 in 300,000 births in the general population. Unlike Tay-Sachs disease, Sandhoff disease is rare in the  Ashkenazi Jewish population, with a prevalence rate estimated at 1 in 1,000,000 (Gravel et al. 2001).
Sandhoff Disease is inherited in an autosomal recessive manner and results from pathogenic variants in the HEXB gene (Bikker et al. 1989; Nakano and Suzuki 1989). It occurs worldwide, with a carrier frequency of 1/278 in the general population, and 1/500 in the Ashkenazi Jewish population (Gravel et al. 2001).

Over 80 pathogenic variants have been reported and include missense, nonsense, splicing, small insertions/deletions and several large deletions. Pathogenic variants have been shown to arise throughout the HEXB gene and were documented in patients from various ethnic and geographic backgrounds such as South Americans (Kleiman et al. 1994), Japanese (Fujimaru et al. 1998), Italian (Zampieri et al. 2009), Arabs from the Middle East (Kaya et al. 2011), Iranians (Aryan et al. 2012), Spanish (Gort et al. 2012), and French (Gaignard et al. 2013).

The HEXB gene encodes the beta-subunit of beta-hexosaminidase A and B isoenzymes, which catalyze the biodegradation of GM2 gangliosides.
Testing Strategy
This test involves bidirectional DNA Sanger sequencing of all coding exons of the HEXB gene. The full coding sequence of each exon plus ~10 bp of flanking DNA on either side are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known pathogenic variants or to confirm research results.
Indications for Test
This test is indicated for patients with symptoms suggestive of GM2 gangliosidosis and reduction or deficiency of both beta-hexosaminidase A and B isoenzyme activities measured in plasma or cultured skin fibroblast; and family members of patients with known pathogenic variants in the HEXB gene.


Official Gene Symbol OMIM ID
HEXB 606873
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Sandhoff Disease 268800

Related Tests

GM2-Gangliosidosis Variant AB via the GM2A Gene
Tay-Sachs Disease via the HEXA Gene


Genetic Counselors
  • Aryan H, Aryani O, Banihashemi K, Zaman T, Houshmand M. 2012. Novel Mutations in Sandhoff Disease: A Molecular Analysis among Iranian Cohort of Infantile Patients. Iran J Public Health 41:112-118. PubMed ID: 23113155
  • Bikker H, van den Berg FM, Wolterman RA, de Vijlder JJ, Bolhuis PA. 1989. Demonstration of a Sandhoff disease-associated autosomal 50-kb deletion by field inversion gel electrophoresis. Hum Genet 81:287-288. PubMed ID: 2921040
  • Fujimaru M, Tanaka A, Choeh K, Wakamatsu N, Sakuraba H, Isshiki G. 1998. Two mutations remote from an exon/intron junction in the beta-hexosaminidase beta-subunit gene affect 3'-splice site selection and cause Sandhoff disease. Hum Genet 103:462-469. PubMed ID: 9856491
  • Gaignard P, Fagart J, Niemir N, Puech JP, Azouguene E, Dussau J, Caillaud C. 2013. Characterization of seven novel mutations on the HEXB gene in French Sandhoff patients. Gene 512:521-526. PubMed ID: 23046579
  • Gort L, de Olano N, Macías-Vidal J, Coll MA; Spanish GM2 Working Group. 2012. GM2 gangliosidoses in Spain: analysis of the HEXA and HEXB genes in 34 Tay-Sachs and 14 Sandhoff patients. Gene 506:25-30. PubMed ID: 22789865
  • Gravel RA, Kaback MM, Proia RL, Sandhoff K, Suzuki K and Suzuki K. 2001. The GM2 Gangliosidoses.  In: Scriver et al. Eds 8 Vol 3 McGraw-Hill, New York, 3827-3877.
  • Kaya N, Al-Owain M, Abudheim N, Al-Zahrani J, Colak D, Al-Sayed M, Milanlioglu A, Ozand PT, Alkuraya FS. 2011. GM2 gangliosidosis in Saudi Arabia: multiple mutations and considerations for future carrier screening. Am J Med Genet A 155A:1281-1284. PubMed ID: 21567908
  • Kleiman FE, de Kremer RD, de Ramirez AO, Gravel RA, Argaraña CE. 1994. Sandhoff disease in Argentina: high frequency of a splice site mutation in the HEXB gene and correlation between enzyme and DNA-based tests for heterozygote detection. Hum Genet 94:279-282. PubMed ID: 8076944
  • Kolter T and Sandhoff K. 2006. Sphingolipid metabolism diseases. Biochim Biophys Acta 1758:2057-79. Review. PubMed ID: 16854371
  • Nakano T and Suzuki K. 1989. Genetic cause of a juvenile form of Sandhoff disease. Abnormal splicing of beta-hexosaminidase beta chain gene transcript due to a point mutation within intron 12. J Biol Chem 264:5155-5158. PubMed ID: 2522450
  • Neote K, McInnes B, Mahuran DJ, Gravel RA. 1990.  Structure and distribution of an Alu-type deletion mutation in Sandhoff disease. J Clin Invest. 86:1524-1531. PubMed ID: 2147027
  • Sandhoff K, Harzer K, Wässle W, Jatzkewitz H. 1971. Enzyme alterations and lipid storage in three variants of Tay-Sachs disease. J Neurochem 18:2469-89. PubMed ID: 5135907
  • Zampieri S, Filocamo M, Buratti E, Stroppiano M, Vlahovicek K, Rosso N, Bignulin E, Regis S, Carnevale F, Bembi B, Dardis A. 2009. Molecular and functional analysis of the HEXB gene in Italian patients affected with Sandhoff disease: identification of six novel alleles. Neurogenetics 10:49-58. PubMed ID: 18758829
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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