INFLUENCE OF SEX OF THE TRANSMITTING PARENT AS WELL AS OF PARENTAL ALLELE SIZE ON THE CTG EXPANSION IN MYOTONIC-DYSTROPHY (DM)

In patients with myotonic dystrophy (DM), the severity of clinical sig ns is correlated with the length of a (CTG)n trinucleotide repeat sequ ence. This sequence tends to expand in subsequent generations. In orde r to examine the kinetics of this process and, in particular, the infl uence of the mutant-allele size and the sex of the transmitting parent , we have studied (CTG)n repeat lengths in the offspring of 38 healthy carriers with small mutations (less than 100 CTG trinucleotides, mean length [CTG]67). In these studies, we found a weakly positive correla tion between the size of the mutation in the carrier parents and that in their offspring. Furthermore, we observed that, in the offspring of male transmitters, repeat lengths exceeding 100 CTG trinucleotides we re much more frequent than in the offspring of carrier females (48 [92 %] of 52 vs. 7 [44%] of 16, P = .0002). Similarly, in genealogical stu dies performed in 38 Dutch DM kindreds, an excess of nonmanifesting ma le transmitters was noted, which was most conspicuous in the generatio n immediately preceding that with phenotypic expression of DM. Thus, t wo separate lines of evidence suggest that the sex of the transmitting parent is an important factor that determines DM allele size in the o ffspring. On the basis of our data, we estimate that when both parents are asymptomatic, the odds are approximately 2:1 that the father carr ies the DM mutation. Because expansion of the CTG repeat is more rapid with male transmission, negative selection during spermatogenesis may be required to explain the exclusive maternal inheritance of severe c ongenital onset DM.