Targeted Next-Generation Sequencing Reveals Novel TTN Mutations Causing Recessive Distal Titinopathy

• DOI: 10.1007/s12035-016-0242-3
• Publication Date: 2016-10-29T07:12:35Z
• Authors: Anni Evilä; Johanna Palmio; Anna Vihola; Marco Savarese; Giorgio Tasca; Sini Penttilä; Sara Lehtinen; Per Harald Jonson; Jan De Bleecker; Peter Rainer; Michaela Auer-Gru...; Jean Pouget; Emmanuelle Salort...; Juan J. Vilchez; Nuria Muelas; Montse Olive; Peter Hackman; Bjarne Udd
• Keywords: Male; 0301 basic medicine; TTN; Titin; Distal myopathy; PHENOTYPES; CALPAIN; Titinopathy; MYOPATHY; Young Adult; 03 medical and health sciences; LARGE FAMILY; Humans; C-TERMINAL TITIN; Connectin; TIBIAL MUSCULAR-DYSTROPHY; High-Throughput Nucleotide Sequencing; Sequence Analysis, DNA; M-BAND; GENE; Pedigree; 3. Good health; Distal Myopathies; Biomedicine; Gene Targeting; Mutation; Female

Tibial muscular dystrophy (TMD) is the first described human titinopathy. It is a mild adult-onset slowly progressive myopathy causing weakness and atrophy in the anterior lower leg muscles. TMD is caused by mutations in the last two exons, Mex5 and Mex6, of the titin gene (TTN). The first reported TMD mutations were dominant, but the Finnish founder mutation FINmaj, an 11-bp insertion/deletion in Mex6, in homozygosity caused a completely different severe early-onset limb-girdle muscular dystrophy 2J (LGMD2J). Later, we reported that not all TMD mutations cause LGMD when homozygous or compound heterozygous with truncating mutation, but some of them rather cause a more severe TMD-like distal disease. We have now performed targeted next-generation sequencing of myopathy-related genes on seven families from Albania, Bosnia, Iran, Tunisia, Belgium, and Spain with juvenile or early adult onset recessive distal myopathy. Novel mutations in TTN Mex5, Mex6 and A-band exon 340 were identified in homozygosity or compound heterozygosity with a frameshift or nonsense mutation in TTN I- or A-band region. Family members having only one of these TTN mutations were healthy. Our results add yet another entity to the list of distal myopathies: juvenile or early adult onset recessive distal titinopathy.