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

Abstract

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.

Is Gene-Size an Issue for the Diagnosis of Skeletal Muscle Disorders?

“…TTN mutations are responsible for a wide spectrum of skeletal muscle disorders with or without an overt cardiac involvement [17]. Skeletal muscle titinopathies are mainly recessive and include congenital myopathies and proximal or distal myopathies with a later onset [17][18][19]. Mutations in the last exons can result in a dominant form, the Tibial Muscular Dystrophy, a late onset distal myopathy [20].…”

“…The different forms of titinopathies show specific progression-related patterns of muscular involvement [18,19,21,56]. In the RYR1-related dominant central core myopathies, MRI studies show a selective involvement of vasti, sartorius and adductor magnus in the thigh and of soleus, gastrocnemii, and peroneal group in the leg with relative sparing of rectus femoris, gracilis, adductor longus and tibialis anterior [57].…”

“…Similarly, the integration of RNAseq with genome sequencing has resulted in an improved diagnostic rate for a wide spectrum of undiagnosed Mendelian diseases [133]. Moreover, the availability of the most appropriate tissue for RNA extraction/analysis further increases the diagnostic rate [18,128]. For skeletal muscle disorders, muscle is the most informative tissue due to the higher expression of disease genes [128].…”

Pathologies musculaires liées à la titine

“…Titinopathies à début juvénile ou tardif Pour la plupart, il s'agit de myopathies autosomiques dominantes associées à des mutations hétérozygotes de TTN (TMD, HMERF), mais des phénotypes récessifs (titinopathie distale juvénile [14], titinopathie de type EmeryDreifuss [15], deux familles avec titinopathie proximale à début adulte [16] ont été rapportés récemment. Les patients décrits jusqu'à présent ne présentent pas d'atteinte cardiaque, et, seulement dans le cas de HMERF, on observe une insuffisance respiratoire importante.…”

“…L'évolution est lente et bénigne, évoluant dans certains cas vers une faiblesse modérée et tardive des muscles proximaux des membres inférieurs. Plus rarement, la présence de deux mutations de TTN à l'état hétérozygote composite est associée à une forme autosomique récessive de TMD à début plus précoce (vers l'âge de 20 ans), appelée TMD juvénile [16,14]. Dans la myopathie des ceintures de type 2J (ou LGMD 2J), le début est précoce, dans l'enfance ou à l'adolescence.…”