Huntington disease (HD) is a neurodegenerative disease that affects approximately 1 in 10,000 individuals of European decent and is characterized by progressive motor impairment and dementia.

HD is associated with an expansion of a CAG tandem repeat in exon 1 of the IT-15 gene on 4p16.3.  HD is a dominant disorder with complete penetrance when the CAG repeat length > 40.  Penetrance is reduced when the CAG repeat length is between 36 and 39.  Chromosomes with < 26 CAG repeats in the IT-15 gene are considered normal and are not at risk to expand to disease alleles when passed on to offspring.  Alleles with between 27 and 35 CAG repeats have never been shown to be associated with the HD phenotype, but are at risk to expand to disease alleles when passed onto offspring.  Although expansions can occur in both maternal and paternal expansions, inheritance of large expansions occurs through paternal inheritance.

Size of the CAG tandem repeat region of the huntingtin gene is routinely determined with PCR analysis of genomic DNA.  PCR primers that exclude the adjacent polymorphic CCG tract are used to unambiguously determine the CAG repeat number.  A second set of PCR primers that includes the adjacent CCG microsatellite polymorphism is used to differentiate two alleles in a patient with an identical CAG repeat number.  Southern blot testing is used to rule-out the presence of a large expansion when the PCR test detects only one allele in a patient sample and when the CCG polymorphism is uninformative. 

The Huntington's Disease Collaborative Research Group (1993) A Novel Gene Containing a Trinucleotide Repeat That is Expanded and Unstable on Huntington's Disease Chromosomes.  Cell, Vol 72:971-983.

Kremer, et al. (1995) Sex-Dependent Mechanisms for Expansion and Contractions of the CAG Repeat on Affected Huntington Disease Chromosomes.  Am. J. Hum. Genet., Vol 57:343-350.

ACMG/ASHG Statement:  Laboratory Guidelines for Huntington Disease Testing.  The American College of Medical Genetics/American Society of Human Genetics Huntington Disease Genetic Testing Working Group (1998).  Am. J. Hum. Genet., Vol 62:1243-1247.

Bruland, et al. (1999) Accurate Determination of the Number of CAG Repeats in the Huntington Disease Gene Using a Sequence-Specific Internal DNA Standard.  Clin. Gnet., Vol 55:198-202.

Guida , et al. (1996) Southern Transfer Protocol for the Confirmation of Huntington Disease. Clin Chem., Vol 42:1711-1712.