Rethinking Genotype and Phenotype Correlations in Polyglutamine Expansion Disorders

Extract

Introduction

Disorders caused by triplet expansions present unique challenges for understanding and correlating the genotype with the clinical phenotype. Currently, there is some confusion over ranges for normal and disease alleles and regarding understanding of penetrance and intermediate alleles. Various centres have adopted different definitions, resulting in varying interpretations of allele sizes and their relationship to phenotype by a particular age. Furthermore, the observation in some trinucleotide repeat (TNR) diseases of new mutations arising from ‘intermediate’ sized alleles has resulted in different interpretations over what is a ‘normal’ and what is a ‘disease’ allele. This has also been accompanied by an emerging recognition that many factors, including genetic changes outside of the causative gene and potentially even environmental features, might influence these classical ‘single gene’ disorders. We have collected data from >80 peer-reviewed manuscripts on the seven disorders associated with expansion of a CAG repeat, as well as consulted with experts in the field on unpublished data, in order to define the normal and disease range of alleles, determine the zone of reduced penetrance, if any, and define the size range for intermediate sized alleles proven molecularly to expand to a CAG size in the disease range. Here we present an approach for the interpretation of allele sizes and their relationship to a phenotype for this class of disorders.