Clinlab Navigator

Huntington Disease Gene Analysis

Huntington disease (HD) is an inherited progressive neurodegenerative disorder characterized by choreiform movements, psychiatric problems, and dementia. Huntington disease is an autosomal dominant disorder that results in diffuse atrophy of the caudate and putamen.

Diagnosis of HD is based upon presence of the typical clinical features and a family history of the disease. Suspected cases can be confirmed by genetic molecular testing. Genetic testing has a  sensitivity of 99% and specificity of  100% for HD. Molecular testing is indicated for confirmation of clinically suspected cases of HD and presymptomatic testing for individuals with a family history of HD and a documented genetic abnormality.Individuals undergoing predictive testing should receive pre and post genetic counseling.

The genetic abnormality in HD is expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the Huntingtin (HTT) gene, which is located on chromosome 4p16.3. This gene codes for huntingtin protein. Mutant huntingtin contains an expanded tract of glutamine residues near its amino terminus, which causes it to form abnormal protein aggregates that cause neuronal cell damage.

Huntingtin is widely expressed throughout the brain, and in other tissues. HD pathology is largely limited to the caudate and putamen. Disease localization may be explained by the binding of mutant huntingtin with Rhes, a small guanine nucleotide-binding protein that is localized in the striatum.

Wild-type HTT genes have 6 to 34 CAG repeat units. More than 35 repeats is associated with disease. Most patients with adult onset HD have alleles with 40 to 50 CAG repeats, while juvenile HD is associated with alleles containing more than 60 repeats. Some patients may have more than 100 CAG repeats. A higher number of CAG repeats is one of the predictors of earlier onset of symptoms.

Disease penetrance is variable in patients with 35 to 39 CAG repeats. Full penetrance occurs with more than 40 repeats. The number of CAG repeats may expand over successive generations, causing earlier onset and more severe disease. Paternal transmission appears to result in greater intergenerational CAG expansion than maternal transmission.

Approximately 1% of patients with typical HD symptoms will not have an abnormal HTT gene. These patients may have  neurodegenerative disease caused by repeat expansions in another gene such as dentatorubral pallidoluysian atrophy, Huntington disease-like syndrome 2, spinocerebellar ataxia type 17, familial prion disease or Friedreich ataxia

PCR is used to detect CAG trinucleotide expansions in exon 1 of the HTT gene. Specimen requirement is a lavender top (EDTA) tube of blood. 

AddThis Social Bookmark Button