Trinucleotide Repeat Disorders - Genetics

Genetics

Trinucleotide repeat disorders generally show genetic anticipation, where their severity increases with each successive generation that inherits them. This is likely explained by the addition of further CAG-repeats in the gene in the progeny of affected individuals. For example, Huntington's disease occurs when there are more than 35 CAG repeats on the gene coding for the protein HTT. A parent with 35 repeats would be considered "normal" and never exhibit any symptoms of the disease. That parent's offspring, however, would be at an increased risk compared to the general population of developing Huntington's, as it would take only the addition of one more CAG codon to cause the production of mHTT (mutant HTT), the protein responsible for disease. Huntington's very rarely occurs spontaneously; it is almost always the result of inheriting the defective gene from an affected parent. That said, sporadic cases of Huntington's do occur, and those individuals with a parent who already has a significant number of CAG repeats in their HTT gene, especially if it approaches the number (36) required for the disease to manifest, are at an increased risk of developing Huntington's despite the lack of any history of the disease in their family. Also, the more repeats, the more severe the disease and the earlier its onset. This explains why individuals that have had Huntington's running in their family for a longer period of time show an earlier age of disease onset and faster disease progression, as mutations that add additional CAG codons become more likely with each successive generation.

Trinucleotide repeat disorders are the result of extensive duplication of a single codon. In fact, the cause is trinucleotide expansion up to a repeat number above a certain threshold level. Huntington's is a good example of this phenomenon, as can be seen in the table on the right.