Somatic mosaicism in sperm is associated with intergenerational (CAG)_n changes in Huntington disease

Abstract

We have analysed the CAG repeat in the Huntington disease (HD) gene in sperm and blood from 20 unrelated HD patients. Although the CAG repeat displayed significant mosaicism in sperm from all individuals, there were marked differences in the degree of repeat instability. Individuals who had either inherited or transmitted an expanded CAG repeat displayed the highest levels of repeat mosaicism, whereas individuals who had inherited or transmitted a contracted repeat had very limited CAG mosaicism in sperm. A strong association between intergenerational change in CAG allele size and the level of sperm repeat mosaicism was determined (P = 0.019). In contrast, neither blood CAG size nor repeat mosaicism in blood, were significantly associated with intergenerational CAG changes. These data suggest the presence of a cis-acting factor, separate from CAG size, that strongly influences the intergenerational behaviour of the CAG repeat. Additional studies are needed to determine whether analysis of CAG mosaicism in sperm is useful for assessing an individual's risk for transmitting large expansions or contractions to his offspring.

Identification and Chromosomal Localization of Human Genes Containing CAG/CTG Repeats Expressed in Testis and Brain

“…We observed a variation of 13 to 17 CAGs for gene 14, and 10 or 11 CAGs for gene 25. This could reflect allelic mosaisism expression observed previously for this kind of gene in human testis (Zühlke et al 1993;Telenius et al 1995;Zhang et al 1995), which may occur in meiosis during spermatogenesis.…”

Huntington's Disease

“…1A). The ability to correlate the length of the CAG expansion to clinical phenotype uncovered the molecular basis for genetic anticipation (Telenius et al 1993;Telenius et al 1995). Anticipation in HD referred to the puzzling phenomenon whereby inheritance of the mutant HTT allele through the male germ line often led to a more severe clinical course than inheritance through the female germ line.…”

MSH2-Dependent Germinal CTG Repeat Expansions Are Produced Continuously in Spermatogonia from DM1 Transgenic Mice

“…A high level of mosaicism was commonly observed in sperm, with this mosaicism overlapping the sizes inherited by the offspring, suggesting that intergenerational instability results mainly from germinal instability in the father (8,12,25,34,38,52,53). However, several studies, including one on fragile X fetuses and one on transmission in Friedreich ataxia families, suggested that intergenerational length changes could also involve a postzygotic instability event (13,14,37).…”