Rethinking genotype and phenotype correlations in polyglutamine expansion disorders.

Abstract

INTRODUCTION Disorders caused by triplet expansions present unique challengesfor understanding and correlating the genotype with the clinicalphenotype. Currently, there is some confusion over ranges fornormal and disease alleles and regarding understanding ofpenetrance and intermediate alleles. Various centres have adopteddifferent definitions, resulting in varying interpretations of allelesizes and their relationship to phenotype by a particular age.Furthermore, the observation in some trinucleotide repeat (TNR)diseases of new mutations arising from ‘intermediate’ sizedalleles has resulted in different interpretations over what is a‘normal’ and what is a ‘disease’ allele. This has also beenaccompanied by an emerging recognition that many factors,including genetic changes outside of the causative gene andpotentially even environmental features, might influence theseclassical ‘single gene’ disorders. We have collected data from >80peer-reviewed manuscripts on the seven disorders associated withexpansion of a CAG repeat, as well as consulted with experts inthe field on unpublished data, in order to define the normal anddisease range of alleles, determine the zone of reduced pene-trance, if any, and define the size range for intermediate sizedalleles proven molecularly to expand to a CAG size in the diseaserange. Here we present an approach for the interpretation of allelesizes and their relationship to a phenotype for this class ofdisorders.CAG SIZE RANGES ASSOCIATED WITH DISEASEThe ranges of allele sizes in the seven disorders is based on the totalnumber of individuals, normal and affected, that have been assessed.This in turn is influenced by the frequency of the disorder as well as,to a lesser extent, the length of time since the gene has been cloned(Table 1) (1–88). The affected range is defined as the range of CAGsdetected in persons with the clinical phenotype of a particulardisorder caused by mutations in the gene in question. The dataavailable to date are shown in Figure 1 (1–88). For spinocerebellarataxia type 1 and 2 (SCA1, SCA2), spinal and bulbar muscularatrophy (SBMA), dentatorubropallidoluysian atrophy (DRPLA) andespecially spinocerebellar ataxia type 6 (SCA6), the small numbersof affected chromosomes examined means that the ranges will likelychange at their margins, as more individuals are assessed (Table 1).Except for SCA6, the similarity between the ranges of disease(>40 CAGs) and normal size alleles at each of the seven TNRdiseases suggests a common mechanism of expansion. However,the interval between normal and disease range can also be usedto divide these seven disorders into two groups. For example,SBMA, SCA6, DRPLA and SCA3 clearly have mutuallyexclusive normal and disease range CAG alleles. On the otherhand, there is no obvious gap between normal and disease rangesfor Huntington’s disease (HD), SCA1 and SCA2 (Fig. 1).PENETRANCE, INDIVIDUALITY AND DISEASEDespite our extensive genetic variability and exposure to differentenvironments, it is remarkable that, for all these disorders, thatCAG size is associated so strongly with age of onset—a criteraitself subject to significant differences in interpretation. A diseasegene has reduced penetrance when a fraction of patients do notmanifest the disorder despite inheriting a known disease-causingmutation (89). However, for many individuals with TNRdiseases, the onset of illness is often late and highly variable. Thuspenetrance is age-dependent. In these instances it is appropriateto define reduced penetrance as occurring if persons haveinherited a mutation in the disease range but lived beyond theexpected lifespan without manifesting any signs of the disease.Reduced penetrance is the one end of the spectrum ofexpression of a disease-causing mutation and is clear evidence ofhow unique individuals accommodate to a particular mutation inthe context of the whole genome, environment and experience.The delineation of the molecular basis of these diseases hasallowed new and definitive approaches to assessment ofpenetrance in this class of disorders. For all of the CAG TNRdiseases combined, the reported instances of non-penetrance arefew, given the large number of individuals molecularly assessed(8,30,44,90–92).