TTN-related limb-girdle muscular dystrophy caused by a homozygous c.107837A>C variant: first report in an African patient

This is the authors' abstract. We don't add key points for this paper.

Tibial muscular dystrophy (TMD) is a late-onset autosomal dominant distal myopathy initially described in the Finnish population and caused by monoallelic, mostly missense, TTN variants. More recently, earlier-onset limb girdle muscular dystrophy phenotypes have been reported in patients carrying biallelic TTN variants. We describe the first African patient homozygous for a previously described TMD related TTN variant presenting with a limb-girdle muscular dystrophy (LGMD) phenotype. The proband, an ambulant 11-year-old boy originally from Libya, presented with progressive lower limb weakness that was first noted at the age of 9 months. He displayed a phenotype characterised by proximal and distal lower-limb weakness that evolved over 10 years into a clear limb-girdle pattern. T1-weighted muscle MRI images revealed fatty replacement of the gluteus maximus, vasti, adductor magnus, soleus, and tibialis anterior muscles. Formal cardiac and pulmonary evaluations were unremarkable, and electromyography depicted a myopathic pattern. Muscle biopsy revealed mild dystrophic changes with fibre size variation, internal nuclei, rimmed vacuoles, with absent calpain-3 expression on western blot. Whole-genome sequencing revealed that the proband is homozygous for the c.107837A>C (p.His35946Pro) pathogenic TTN variant. His first-degree consanguineous parents are heterozygous for the variant, yet they remain asymptomatic. This case expands the genetic spectrum of biallelic TTN variants associated with LGMD R10.