Parental repeat length instability in myotonic dystrophy type 1 pre- and protomutations

Abstract

Myotonic dystrophy type 1 (DM1) is caused by a CTG trinucleotide repeat expansion on chromosome 19q13.3. While DM1 premutation (36-50 repeats) and protomutation (51-80 repeats) allele carriers are mostly asymptomatic, offspring is at risk of inheriting expanded, symptom-associated, (CTG)n repeats of n > 80. In this study we aimed to evaluate the intergenerational instability of DM1 pre- and protomutation alleles, focussing on the influence of parental gender. One hundred and forty-six parent-child pairs (34 parental premutations, 112 protomutations) were retrospectively selected from the DM1 patient cohort of the Maastricht University Medical Center+. CTG repeat size of parents and children was determined by (triplet-primed) PCR followed by fragment length analysis and Southern blot analysis. Fifty-eight out of eighty-one (71.6%) paternal transmissions led to a (CTG)n repeat of n > 80 in offspring, compared with 15 out of 65 (23.1%) maternal transmissions (p < 0.001). Repeat length instability occurred for paternal (CTG)n repeats of n ≥ 45, while maternal instability did not occur until (CTG)n repeats reached a length of n ≥ 71. Transmission of premutations caused (CTG)n repeats of n > 80 in offspring only when paternally transmitted (two cases), while protomutations caused (CTG)n repeats of n > 80 in offspring in 71 cases, of which 56 (78.9%) were paternally transmitted. In conclusion, our data show that paternally transmitted pre- and protomutations were more unstable than maternally transmitted pre- and protomutations. For genetic counseling, this implies that males with a small DMPK mutation have a higher risk of symptomatic offspring compared with females. Consequently, we suggest addressing sex-dependent factors in genetic counseling of small-sized CTG repeat carriers.

Fig. 1. Included premutation and protomutation allele carrying parents.

Individuals with an identified premutation ((CTG)n, n = 36–50) or protomutation ((CTG)n, n = 51–80), tested between 1993 and 2017, were selected from the myotonic dystrophy type 1 (DM1) patient cohort database of the Clinical Genetics laboratory of the Maastricht University Medical Center+. Intergenerational instability of the CTG repeat length is displayed for both groups separately. Out of 146 pre- and protomutation transmissions, 97 transmissions regard first-born offspring.

Fig. 2. Relationship between parental CTG repeat length and myotonic dystrophy type 1 (DM1) status in offspring.

The diagrams demonstrate the relationship between parental CTG repeat length and DM1 status in offspring, for DM1 premutation ((CTG)n, n = 36–50) and protomutation ((CTG)n, n = 51–80) allele carrying parents. DM1 status in offspring is based on a cut-off value of (CTG)n, n > 80. a Paternal transmission. b Maternal transmission.

Fig. 3. Relationship between parental CTG repeat length and CTG repeat length in offspring.

Charts have been categorized by parental gender. DM1 status is based on a cut-off value of (CTG)n, n > 80. The values above each pie chart represent parental CTG repeat length.