Influence of sex of the transmitting parent as well as of parental allel size on the CTG expansion in myotonic dystrophy (DM)

• Published in: American journal of human genetics 1993-11, Vol.53:5
• Main Authors: Brunner, H.G., Brueggenwirth, H.T., Nillesen, W., Hamel, B.C.J., Hoppe, R.L.E., Oost, B.A. van, Ropers, H.H., Smeets, H.J.M., Jansen, G., Die, C.E.M. de, Hoeweler, C.J. Wieringa, B.
• Format: Article
• Language: English
• Subjects: BASIC BIOLOGICAL SCIENCES; DISEASES; GENE MUTATIONS; HEREDITARY DISEASES; MUSCLES; MUTATIONS 550400 > Genetics; SEX DEPENDENCE
• ISSN: 0002-9297; 1537-6605

In patients with myotonic dystrophy (DM), the severity of clinical signs is correlated with the length of a (CTG)[sub n] trinucleotide repeat sequence. This sequence tends to expand in subsequent generations. In order to examine the kinetics of this process and, in particular, the influence of the mutant-allele size and the sex of the transmitting parent, the authors have studied (CTG)[sub n] repeat lengths in the offspring of 38 healthy carriers with small mutations (less than 100 CTG trinucleotides, mean length [CTG][sub 67]). In these studies, the authors found a weakly positive correlation between the size of the mutation in the carrier parents and that in their offspring. Furthermore, the authors observed that, in the offspring of male transmitters, repeat lengths exceeding 100 CTG trinucleotides were much more frequent than in the offspring of carrier females (48 [92%] of 52 vs. 7 [44%] of 16, P = .0002). Similarly, in genealogical studies performed in 38 Dutch DM kindreds, an excess of nonmanifesting male transmitters was noted, which was most conspicuous in the generation immediately preceding that with phenotypic expression of DM. Thus, two separate lines of evidence suggest that the sex of the transmitting parent is an important factor that determines DM allele size in the offspring. On the basis of the data, the authors estimate that when both parents are asymptomatic, the odds are approximately 2:1 that the father carries 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 congenital onset DM. 42 refs., 1 fig., 2 tabs.