Molecular analysis of new mutations for Huntington's disease: intermediate alleles and sex of origin effects

Abstract

Huntington's disease (HD) is associated with expansion of a CAG repeat in a novel gene. We have assessed 21 sporadic cases of HD to investigate sequential events underlying HD. We show the existence of an intermediate allele (IA) in parental alleles of 30-38 CAG repeats in the HD gene which is greater than usually seen in the general population but below the range seen in patients with HD. These IAs are meiotically unstable and in the sporadic cases, expand to the full mutation associated with the phenotype of HD. This expansion has been shown to occur only during transmission through the male germline and is associated with advanced paternal age. These findings suggest that new mutations for HD are more frequent than prior estimates and indicate a previously unrecognized risk of inheriting HD to siblings of sporadic cases of HD and their children.

Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes

“…Intermediate alleles (IAs), also known as large normal alleles, are between 27 and 35 CAG repeats and may give rise to de novo expansions on transmission. [4][5][6][7][8] Individuals with IAs will not develop HD, however, their offspring are at risk of inheriting a CAG tract that has expanded into the pathogenic range. Although the size of the CAG tract contributes to instability and is associated with age of onset, there is significant phenotypic variation among individuals with identical repeat lengths.…”

“…1,9 Various other factors, including non-CAG genetic modifiers, have been suggested to have a role in expansion and the age of onset of disease symptoms. 5,7,10 Several studies have attempted to make use of genome-wide analyses in order to identify genetic modifiers and better understand HD aetiology and pathogenesis. [11][12][13] A number of processes were implicated in early disease pathogenesis; however, specific genetic modifiers are still under investigation.…”

Genetic fitness in Huntington's Disease and Spinocerebellar Ataxia 1: a population genetics model for CAG repeat expansions

“…The HD mutation was found to be in linkage disequilibrium with 2 major haplotypes and also to be carried by a plethora of different haplotypes, indicating that new mutations do not constitute as rare an event as was previously thought (MacDonald et al, 1992). Indeed, new HD mutations have been documented by CAG typing (Myers et al, 1993;Goldberg et al, 1993). Several authors have pointed out that haplotypes overrepresented in HD are found in the normal population with repeat numbers at the upper end of the normal range (Squitieri et al, 1994;Almqvist et al, 1995).…”

Spinocerebellar ataxia 1 (SCA1) in the Japanese: Analysis of CAG trinucleitide repeat expansion and instability of the repeat for paternal transmission

“…Despite this same gene configuration with SCA1, such alleles do not seem to be a pre-mutation because they distribute selectively at the lower limit of normal alleles. On the other hand, analysis of a new mutation in the HD gene strongly indicates that pre-mutation does occur from a pool of normal alleles with limited instability, but having repeats larger than those of typical normal alleles (Goldberg et aL, 1993). In SCA1, CAT interruption within the CAG repeat tract is considered to stabilize an SCA1 allele on replication .…”