TTN-Related Muscular Dystrophies, LGMD, and TMD, in an Estonian Family Caused by the Finnish Founder Variant.

BACKGROUND AND OBJECTIVES: Tibial muscular dystrophy (TMD) is an autosomal dominant, slowly progressive late-onset distal myopathy. TMD was first described in 1991 by Udd et al. in Finnish patients, who were later found to harbor a heterozygous unique 11-bp insertion/deletion in the last exon of the TTN gene-the Finnish founder variant (FINmaj). In homozygous state or compound heterozygosity with a truncating variant, the FINmaj causes early-onset recessive titin-related limb-girdle muscular dystrophy type 10 (LGMD R10). So far, the FINmaj variant has not been detected outside the Finnish population.

METHODS: We describe an Estonian family presenting both early-onset LGMD R10 and late-onset TMD. The index patient underwent trio exome sequencing (ES), muscle biopsy, and RNA sequencing. The detected variants were validated by Sanger sequencing. Muscle MRI was performed in all affected individuals.

RESULTS: Trio ES revealed 2 heterozygous variants in the TTN gene: (NM_001267550.2):c.107780_107790delinsTGAAAGAAAAA, p.(Glu35927_Trp35930delinsValLysGluLys) (FINmaj variant, paternally inherited) and (NM_001267550.2):c.64672+2dup (maternally inherited) in trans in the proband. Familial segregation analysis revealed the same biallelic variants in the younger affected sister and heterozygous FINmaj in the father. We characterized the effect of the splice variant by RNA sequencing, proving that it causes an intronic retention resulting in a premature stop codon. Muscle histology of the proband showed myopathic changes. Muscle MRI of both individuals with LGMD R10 showed early degenerative changes in tibialis anterior and in hypotrophy of distal hamstrings. Muscle MRI of the father with TMD, at the age of 38 years, showed early minimal fatty degeneration in the peroneus longus and right tibialis anterior muscles.

DISCUSSION: For the first time, we have detected the FINmaj variant in the Estonian population. We report an Estonian family without any known Finnish ancestry for many generations, with 2 siblings harboring FINmaj in a compound with a splice site variant and their father with heterozygous FINmaj. It is currently not known whether the FINmaj is originally Estonian or Finnish ancestry. Further population studies in Estonia to establish the frequency of FINmaj in the population are ongoing and will solve the quest.