Huntington's Disease Trinucleotide Repeat Sizing

Background

Huntington's Disease (HD) is an autosomal dominant, progressive neurodegenerative disorder characterized by motor disturbance, cognitive loss, and psychiatric manifestations, which usually manifests at around 40 to 50 years of age. It has an incidence of about 1 in 10,000 individuals of European descent. In 5 - 10% of cases, HD is expressed in juveniles, typically presenting with more severe symptoms and a more rapid course. HTT is the gene implicated in HD and contains a normally polymorphic trinucleotide CAG repeat region in the first exon. Normal individuals have between 6 and 35 copies of this repeat. Affected individuals have an expanded repeat region, usually 36 to 121 copies of the repeat. The penetrance of the CAG expansion is not complete, therefore showing variability in the severity of disease symptoms. Individuals with a CAG repeat size of 30 to 35 do not manifest Huntington's Disease themselves, however, the risk that their offspring will develop HD may be increased, particularly from paternal transmission of the gene.

OMIM: 613004

Clinical Unity

Detection of CAG expansions in the HTT gene that lead to Huntington's Disease. The test is done on peripheral blood specimens for confirmation of clinical diagnosis, carrier status or presymptomatic testing.

Methodology

Determination of an expanded trinucleotide CAG repeat region is based on PCR amplification of the Huntingtin (HTT) gene using a pair of primers specific for the surrounding region. The product size is determined using a size standard, and CAG repeat number is calculated.

Loci Tested

HTT exon 1 variable region

Specimen Requirements

Peripheral blood collected in EDTA (purple top) is preferred, 3-10mL.

Turnaround Time

Within 3-5 weeks of receipt

CPT

81401

Shipment Must Include

Specimen
Requisition form
Patient pathology report
Presymptomatic Patient Consent Form or Symptomatic Patient Consent Form

References

  1. The Huntington Disease Collaborative Research Group. A Novel Gene Containing a Trinucleotide Repeat That is Expanded and Unstable on Huntington's Disease Chromosomes. Cell, vol. 72, p. 971-983 (1993)
  2. Valdes, J., Tagle, D., Elmer, L., and Collins, F. A Simple Non-radioactive Method for Diagnosis of Huntington's Disease. Human Molecular Genetics, vol. 2, p. 633-634 (1993)
  3. Goldberg, Y., Andrew, S., Clarke, L., and Hayden, M. A PCR Method for Accurate Assessment of Trinucleotide Repeat Expansion in Huntington Disease. Human Molecular Genetics, vol. 2, p. 635-636 (1993)
  4. Riess, O., Noerremoelle, A., Soerensen, S., and Epplen, J. Improved PCR Conditions for the Stretch of (CAG)n Repeats Causing Huntington's Disease. Human Molecular Genetics, vol. 2, p.637 (1993)
  5. Telenius, H., Kremer, H., Theilmann, J., Andrew, S., Almqvist, E., Anvret, M., Greenberg, C., Greenberg, J., Lucotte, G., Squitieri, F., Starr, E., Goldberg, Y., and Hayden, M. Molecular Analysis of Juvenile Huntington Disease: The Major Influence on (CAG)n Repeat Length is the Sex of the Affected Parent. Human Molecular Genetics, vol. 2, p. 1535-1540 (1993)
  6. Human Molecular Genetics, vol. 2, p. 1535-1540 (1993)
  7. Andrew, S., Goldberg, Y., Theilmann, J., Zeisler, J., and Hayden, M. A CCG Repeat Polymorphism Adjacent to the CAG Repeat in the Huntington Disease Gene: Implications for Diagnostic Accuracy and Predictive Testing. Human Molecular Genetics, vol. 3, p. 65-67 (1994)
  8. Chong, S., Almqvist, E., Telenius, H., LaTray, L., Nichol, K., Bourdelat-Parks, B., Goldberg, Y., Haddad, B., Richards, F., Sillence, D., Greenberg, C., Ives, E., Van den Engh, G., Hughes, M., and Hayden, M. Contribution of DNA Sequence and CAG Size to Mutation Frequencies of Intermediate Alleles for Huntington Disease: Evidence from Single Sperm Analyses. Human Molecular Genetics, vol. 6, p. 301-309 (1997)
  9. Brinkman, R., Mezei, M., Theilmann, J., Almqvist, E., and Hayden, M. The Likelihood of Being Affected with Huntington Disease by a Particular Age, for a Specific CAG Size. American Journal of Human Genetics, vol. 60, p. 1202-1210 (1997)