GAMETIC BUT NOT SOMATIC INSTABILITY OF CAG REPEAT LENGTH IN HUNTINGTONS-DISEASE

Instability of a CAG repeat in 4p16.3 has been found in Huntington's d isease (HD) chromosomes. Unlike a similar repeat in the fragile X synd rome, the expanded HD repeat showed no evidence of somatic instability in a comparison of blood, lymphoblast, and brain DNA from the same pe rsons. Four pairs of monozygotic HD twins displayed identical CAG repe at lengths suggesting that repeat size is determined in gametogenesis. In contrast with the fragile X syndrome and with HD somatic tissue, m osaicism was readily detected as a diffuse spread of repeat lengths in DNA from HD sperm samples. Typically, the modal repeat size was large r in the sperm DNA than in corresponding lymphoblast DNA, with the gre atest degree of gametic mosaicism coinciding with the longest somatic CAG repeats. These data indicate that the developmental timing of repe at instability appears to differ between HD and fragile X syndrome, an d that the fundamental mechanisms leading to repeat expansion may ther efore be distinct.