Population frequency of myotonic dystrophy: higher than expected frequency of myotonic dystrophy type 2 (DM2) mutation in Finland

Abstract

Myotonic dystrophy (DM) is the most common adult-onset muscular dystrophy with an estimated prevalence of 1/8000. There are two genetically distinct types, DM1 and DM2. DM2 is generally milder with more phenotypic variability than the classic DM1. Our previous data on co-segregation of heterozygous recessive CLCN1 mutations in DM2 patients indicated a higher than expected DM2 prevalence. The aim of this study was to determine the DM2 and DM1 frequency in the general population, and to explore whether the DM2 mutation functions as a modifier in other neuromuscular diseases (NMD) to account for unexplained phenotypic variability. We genotyped 5535 Finnish individuals: 4532 normal blood donors, 606 patients with various non-myotonic NMD, 221 tibial muscular dystrophy patients and their 176 healthy relatives for the DM2 and DM1 mutations. We also genotyped an Italian idiopathic non-myotonic proximal myopathy cohort (n = 93) for the DM2 mutation. In 5496 samples analyzed for DM2, we found three DM2 mutations and two premutations. In 5511 samples analyzed for DM1, we found two DM1 mutations and two premutations. In the Italian cohort, we identified one patient with a DM2 mutation. We conclude that the DM2 mutation frequency is significantly higher in the general population (1/1830; P-value = 0.0326) than previously estimated. The identification of DM2 mutations in NMD patients with clinical phenotypes not previously associated with DM2 is of particular interest and is in accord with the high overall prevalence. On the basis of our results, DM2 appears more frequent than DM1, with most DM2 patients currently undiagnosed with symptoms frequently occurring in the elderly population.

Figure 1

Representative results for DM2 mutation genotyping by PCR and RP-PCR. PCR across the (CCTG)_DM2 in intron 1 of ZNF9 showed either a single amplifiable allele (a) or two amplifiable alleles (b), which excludes DM2 mutation. A patient with DM2 mutation from the population cohort showed a peak pattern in ZNF9 RP-PCR characteristic for the DM2 (CCTG)_n repeat expansion mutation (c and d). In the zoomed-in figure (d) adjacent stutter peaks can be seen with base pair difference of 4 bp. Enlarged unstable (but not actually expanded) DM2 alleles have a distinct pattern in RP-PCR (e and f). In the zoomed-in figure (f), the stutter peaks can be seen, but the pattern ends rapidly. Figures (g) and (h) show a typical example of a DM2 negative sample in RP-PCR. Stutter peaks characteristic to DM2 mutation are not seen in the zoomed-in figure (h).

Figure 1

Representative results for DM2 mutation genotyping by PCR and RP-PCR. PCR across the (CCTG)_DM2 in intron 1 of ZNF9 showed either a single amplifiable allele (a) or two amplifiable alleles (b), which excludes DM2 mutation. A patient with DM2 mutation from the population cohort showed a peak pattern in ZNF9 RP-PCR characteristic for the DM2 (CCTG)_n repeat expansion mutation (c and d). In the zoomed-in figure (d) adjacent stutter peaks can be seen with base pair difference of 4 bp. Enlarged unstable (but not actually expanded) DM2 alleles have a distinct pattern in RP-PCR (e and f). In the zoomed-in figure (f), the stutter peaks can be seen, but the pattern ends rapidly. Figures (g) and (h) show a typical example of a DM2 negative sample in RP-PCR. Stutter peaks characteristic to DM2 mutation are not seen in the zoomed-in figure (h).