Autosomal dominant tibial muscular dystrophy in Estonia

Abstract

Aim: Tibial muscular dystrophy (TMD; MIM#600334, ORPHA:609) is an adult-onset, slowly progressive distal myopathy resulting from dominant variants in exon 364 of the TTN gene. The Finnish founder variant (FINmaj), characterized by an 11-bp insertion/deletion, causes autosomal dominant (AD) TMD in heterozygous individuals. Our aim was to assess the prevalence and origin of the FINmaj variant within the Estonian population. Methods: We reanalyzed next-generation sequencing panels and whole-exome sequencing data from 2014 to 2025 to identify individuals carrying the FINmaj variant. The study included three cohorts: Tartu University Hospital (n = 15,178), West Tallinn Central Hospital (n = 52), and the Estonian Genome Center (n = 4,776). Most carriers of the FINmaj variant underwent muscle magnetic resonance imaging (MRI) and haplotype analysis. Results: We identified 13 individuals from five families with the heterozygous FINmaj variant, including two individuals with autosomal recessive limb-girdle muscular dystrophy-10 and eleven with AD TMD. By the age of 50, all patients diagnosed with TMD showed symptoms of distal myopathy and characteristic MRI findings. The carrier frequency of the FINmaj variant in the Estonian cohort was one in 3,036, with no carriers in the Estonian Genome Center cohort. The average haplotype length was estimated to be ~4.1 Mb in Estonians, compared to ~5 Mb in Finns. Conclusion: AD TMD is one of the most prevalent but underdiagnosed hereditary muscle diseases in the Estonian population. Since Estonian patients exhibit an estimated shorter haplotype length than Finnish patients, the FINmaj variant likely originated in Estonia before spreading to Finland.