High frequency of co-segregating CLCN1 mutations among myotonic dystrophy type 2 patients from Finland and Germany

Abstract

Based on previous reports the frequency of co-segregating recessive chloride channel (CLCN1) mutations in families with myotonic dystrophy type 2 (DM2) was suspected to be increased. We have studied the frequency of CLCN1 mutations in two separate patient and control cohorts from Germany and Finland, and for comparison in a German myotonic dystrophy type 1 (DM1) patient cohort. The frequency of heterozygous recessive chloride channel (CLCN1) mutations is disproportionally higher (5%) in currently diagnosed DM2 patients compared to 1.6% in the control population (p = 0.037), while the frequency in DM1 patients was the same as in the controls. Because the two genes segregate independently, the prevalence of CLCN1 mutations in the total DM2 patient population is, by definition, the same as in the control population. Our findings are, however, not based on the total DM2 population but on the currently diagnosed DM2 patients and indicate a selection bias in molecular diagnostic referrals. DM2 patients with co-segregating CLCN1 mutation have an increased likelihood to be referred for molecular diagnostic testing compared to DM2 patients without co-segregating CLCN1 mutation.

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

“…Further evidence for a large proportion of undiagnosed DM2 patients came from our study on diagnosed DM2 patients showing a disproportionally high number of co-segregating heterozygous recessive CLCN1 mutations. 28 This study directly suggested that DM2 patients with co-segregating CLCN1 could be more easily identified and diagnosed than DM2 patients without the modifier allele, and consequently that the majority of DM2 patients remains undiagnosed even in clinical centers with considerable experience with DM2. Our present study investigated the prevalence of the DM2 and DM1 mutations in a cohort of 5535 individuals consisting of anonymous blood donors and patients with various determined and undetermined neuromuscular disorders with exclusion of any myotonic symptoms.…”

“…Since the availability of DM2 molecular diagnostics, our experience indicated that DM2 is far more common than previously estimated. 27,28 Milder phenotypes with prominent myalgia may easily be misdiagnosed as fibromyalgia, 27 and patients with onset of slowly progressive proximal muscle weakness after age 70 years may not be referred for neuromuscular investigations. Further evidence for a large proportion of undiagnosed DM2 patients came from our study on diagnosed DM2 patients showing a disproportionally high number of co-segregating heterozygous recessive CLCN1 mutations.…”

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

“…In the cases described, co-segregation of the CCTG expansion in the first intron of zinc finger protein-9 and a CLCN-1 mutation produced more severe myotonia than is commonly encountered in myotonic dystrophy type II. However, the number of cases was too small for this finding to be statistically significant (Suominen et al, 2008). It is therefore not yet established if the presence of a CLCN-1 mutation is a genetic modifier of the myotonic dystrophy type II phenotype.…”

Colocalization of ribonuclear inclusions with muscle blind like-proteins in a family with myotonic dystrophy type 2 associated with a short CCTG expansion

“…Southern blot analysis on patient 3 showed a large expanded allele of approximately 2.5 kb. Each patient was proven negative for mutations in CLCN1 gene coding for skeletal muscle chloride channel, known to possibly worsen the DM2 clinical phenotype [9].…”