Characteristics of intergenerational contractions of the CTG repeat in myotonic dystrophy.

In myotonic dystrophy (DM), the size of a CTG repeat in the DM kinase gene generally increases in successive generations with clinical evidence of anticipation. However, there have also been cases with an intergenerational contraction of the repeat. We examined 1,489 DM parent-offspring pairs, of which 95 (6.4%) showed such contractions in peripheral blood leukocytes (PBL). In 56 of the 95 pairs, clinical data allowed an analysis of their anticipation status. It is surprising that anticipation occurred in 27 (48%) of these 56 pairs, while none clearly showed a later onset of DM in the symptomatic offspring. The contraction occurred in 76 (10%) of 753 paternal transmissions and in 19 (3%) of 736 maternal transmissions. Anticipation was observed more frequently in maternal (85%) than in paternal (37%) transmissions (P < .001). The parental repeat size correlated with the size of intergenerational contraction (r2 = .50, P << .001), and the slope of linear regression was steeper in paternal (-.62) than in maternal (-.30) transmissions (P << .001). Sixteen DM parents had multiple DM offspring with the CTG repeat contractions. This frequency was higher than the frequency expected from the probability of the repeat contractions (6.4%) and the size of DM sib population (1.54 DM offspring per DM parent, in 968 DM parents). We conclude that (1) intergenerational contractions of the CTG repeat in leukocyte DNA frequently accompanies apparent anticipation, especially when DM is maternally transmitted, and (2) the paternal origin of the repeat and the presence of the repeat contraction in a sibling increase the probability of the CTG repeat contraction.

[1]  E. Zackai,et al.  Paternal transmission of congenital myotonic dystrophy. , 1994, Journal of medical genetics.

[2]  T. Miki,et al.  A case of paternally inherited congenital myotonic dystrophy. , 1994, Journal of medical genetics.

[3]  C. Richards,et al.  Effects of the sex of myotonic dystrophy patients on the unstable triplet repeat in their affected offspring , 1994, Neurology.

[4]  Tetsuo Ashizawa,et al.  Somatic instability of CTG repeat in myotonic dystrophy , 1993, Neurology.

[5]  H. Brunner,et al.  Influence of sex of the transmitting parent as well as of parental allele size on the CTG expansion in myotonic dystrophy (DM). , 1993, American journal of human genetics.

[6]  L. Edström,et al.  Larger expansions of the CTG repeat in muscle compared to lymphocytes from patients with myotonic dystrophy. , 1993, Human molecular genetics.

[7]  G. Danieli,et al.  (CTG)n triplet mutation and phenotype manifestations in myotonic dystrophy patients. , 1993, Biochemical medicine and metabolic biology.

[8]  E. Mariman,et al.  No imprinting involved in the expression of DM-kinase mRNAs in mouse and human tissues. , 1993, Human molecular genetics.

[9]  C. Junien,et al.  Myotonic dystrophy: absence of CTG enlarged transcript in congenital forms, and low expression of the normal allele. , 1993, Human molecular genetics.

[10]  L. Surh,et al.  Effect of the myotonic dystrophy (DM) mutation on mRNA levels of the DM gene , 1993, Nature Genetics.

[11]  I. Lerer,et al.  Negative expansion of the myotonic dystrophy unstable sequence. , 1993, American journal of human genetics.

[12]  W. Reardon,et al.  Size of the unstable CTG repeat sequence in relation to phenotype and parental transmission in myotonic dystrophy. , 1993, American journal of human genetics.

[13]  J. Emparanza,et al.  Sex-related difference in intergenerational expansion of myotonic dystrophy gene , 1993, The Lancet.

[14]  C. Junien,et al.  Myotonic dystrophy: size- and sex-dependent dynamics of CTG meiotic instability, and somatic mosaicism. , 1993, American journal of human genetics.

[15]  C. Caskey,et al.  Relationship between parental trinucleotide GCT repeat length and severity of myotonic dystrophy in offspring. , 1993, JAMA.

[16]  R. Gibbs,et al.  Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy. , 1993, Science.

[17]  D. Shaw,et al.  A study of DNA methylation in myotonic dystrophy. , 1993, Journal of medical genetics.

[18]  I. Glass,et al.  Direct diagnosis of myotonic dystrophy with a disease-specific DNA marker. , 1993, The New England journal of medicine.

[19]  A. Hunter,et al.  Reduction in size of the myotonic dystrophy trinucleotide repeat mutation during transmission. , 1993, Science.

[20]  C. Caskey,et al.  Failure in detecting mRNA transcripts from the mutated allele in myotonic dystrophy muscle. , 1993, Biochemistry and molecular biology international.

[21]  I. MacDonald,et al.  Decrease in the size of the myotonic dystrophy CTG repeat during transmission from parent to child: implications for genetic counselling and genetic anticipation. , 1993, American journal of medical genetics.

[22]  C. Junien,et al.  Different sex-dependent constraints in CTG length variation as explanation for congenital myotonic dystrophy , 1993, The Lancet.

[23]  A. Donnelly,et al.  Explanation for exclusive maternal origin for congenital form of myotonic dystrophy , 1993, The Lancet.

[24]  H. Smeets,et al.  Presymptomatic diagnosis of myotonic dystrophy. , 1992, Journal of medical genetics.

[25]  L. Surh,et al.  The correlation of age of onset with CTG trinucleotide repeat amplification in myotonic dystrophy. , 1992, Journal of medical genetics.

[26]  R. Winqvist,et al.  Unstable DNA may be responsible for the incomplete penetrance of the myotonic dystrophy phenotype. , 1992, Human molecular genetics.

[27]  E. Boerwinkle,et al.  Anticipation in myotonic dystrophy , 1992, Neurology.

[28]  E. Boerwinkle,et al.  Anticipation in myotonic dystrophy , 1992, Neurology.

[29]  W. Reardon,et al.  Anticipation in myotonic dystrophy: new light on an old problem. , 1992, American journal of human genetics.

[30]  R. Korneluk,et al.  Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy , 1992, Nature Genetics.

[31]  W. Reardon,et al.  Unstable DNA sequence in myotonic dystrophy , 1992, The Lancet.

[32]  C. Amemiya,et al.  Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. , 1992, Science.

[33]  T. Ashizawa,et al.  An unstable triplet repeat in a gene related to myotonic muscular dystrophy. , 1992, Science.

[34]  David E. Housman,et al.  Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member , 1992, Cell.

[35]  C. Amemiya,et al.  Cloning of the essential myotonic dystrophy region and mapping of the putative defect , 1992, Nature.

[36]  P. Jong,et al.  Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy , 1992, Nature.

[37]  David E. Housman,et al.  Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy , 1992, Nature.

[38]  P. Harper,et al.  Genetic risks for children of women with myotonic dystrophy. , 1991, American journal of human genetics.

[39]  J. Geraedts,et al.  Anticipation in myotonic dystrophy: fact or fiction? , 1989, Brain : a journal of neurology.

[40]  L. Penrose.  The problem of anticipation in pedigrees of dystrophia myotonica. , 1948, Annals of eugenics.