Genetic anticipation reduced penetrance variable expressivity in Huntingtons disease
Anticipation is the term describing the earlier onset of signs and symptoms in successive generations of affected individuals in the same family.
Its molecular basis lies in the expansion of the CAG trinucleotide repeat size as the altered huntingtin or HTT gene is passed from one generation to the next.
Huntington’s disease status (affected, unaffected, at risk) is associated with the size of the CAG trinucleotide repeat. In huntingtin, a normal repeat size corresponds to fewer than 26 CAG repeats.
This size is not associated with increased risk of Huntington’s disease in the allele carrier or his/her offspring. In contrast, a huntingtin copy containing 40 or more CAG repeats is classified as fully penetrant and is associated with 50% risk of disease in the offspring.
A CAG repeat size ranging from 27 to 35 repeats is classified as intermediate, and it is associated with increased risk of disease in the offspring, but no increased disease risk in the carrier of the expanded allele.
A repeat count of 36 to 39 is known to have reduced penetrance (the mutation carrier may or may not be affected) and 50% risk of disease in the offspring.
Variable expressivity refers to the degree to which Huntington’s disease is expressed in an individual.
One example of this phenomenon is the association between CAG repeat size and age at onset of the disease.
Individuals with huntingtin alleles containing 60 or more CAG repeats commonly have very young onset, before the age of 20 years.