Why the study?
The FINmaj variant in TTN causes early-onset LGMD R10, but had not been detected outside the Finnish population.
This study reports the first detection of the Finnish founder variant (FINmaj) in the TTN gene outside the Finnish population, in an Estonian family with muscular dystrophy.
Extends FINmaj TTN variant distribution beyond Finland; hypothesis-generating for expanded screening in non-Finnish muscular dystrophy.
Background and Objectives: 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: 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.
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Õunap et al. (2024) studied this question.
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