Genetic advances in sporadic inclusion body myositis

To describe recent developments in the genetics of sporadic inclusion body myositis (sIBM).

Genes located within major histocompatibility complex regions remain the strongest genetic association with sIBM. The rs10527454 polymorphism in the TOMM40 gene seems to have a disease modifying effect on sIBM by delaying the onset of symptoms, and this effect may be enhanced by the APOE ε3/ε3 genotype. Rare variants in the VCP and SQSTM1 genes have been identified in sIBM patients in two studies using targeted next-generation sequencing and whole-exome sequencing. Two studies have confirmed the correlation between the amount of cytochrome c oxidase -deficient fibres and the proportion of mitochondrial DNA (mtDNA) deletions in sIBM. Some rare variants in mtDNA-related nuclear genes have also been reported.

There have been advances in the genetics of sIBM over the past 2 years facilitated by the use of next-generation sequencing. Genes that cause hereditary IBM, which has clinical or pathological features resembling sIBM, have provided clues to the genetic basis of sIBM. To date, genes located in major histocompatibility complex regions and genes involved in protein homeostasis or mtDNA maintenance have been implicated in sIBM. Whole-exome sequencing-association studies, RNA sequencing, and whole-genome sequencing in large sIBM cohorts will be key tools to unravel the genetics of sIBM and its contribution to disease aetiopathogenesis.