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A novel c.515delC HSPB8-multisystem proteinopathy associated with inclusion body myopathy with cardiomyopathy

Tan, J.; Duong, H.; Milone, M.; Gibbs, L.; Tedesco, B.; Poletti, A.; Kimonis, V.

2024-07-18 genetic and genomic medicine
10.1101/2024.07.17.24305631 medRxiv
Show abstract

Mutations in the HSPB8, or heat shock protein family B (small) member 8, is a member of the chaperone-assisted selective autophagy complex and has recently been associated with rimmed vacuolar myopathy. We report a family with a HSPB8 rimmed vacuolar myopathy caused by a novel c.515delC variant with progressive muscle weakness, pathological findings of rimmed vacuoles of muscle biopsy, and one individual who died of cardiomyopathy. Whole exome sequencing analyses revealed a c.515delC, resulting in a translational frameshift expected to elongate the protein by an additional 49 amino acid tail. We reviewed the clinical characteristics of all reported patients (N= 26, 15 males and 11 females) in the literature, and performed a genotype/phenotype analysis. Males in the families appeared to present with an earlier age of onset, more severe muscle weakness compared to females, and a higher prevalence of other organ system complications including cardiomyopathy in two males. In conclusion, this family expands the phenotype/genotype correlations in HSPB8-associated myopathy with rimmed vacuoles and c.515 delC. We note that c.515 appears to be a hot spot, and the phenotype appears to be more severe in males in this disease, with an earlier onset of the myopathy.

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