Targeted sequencing and identification of genetic variants in sporadic inclusion body myositis

Abstract

Sporadic inclusion body myositis (sIBM) has clinical, pathologic and pathomechanistic overlap with some inherited muscle and neurodegenerative disorders. In this study, DNA from 79 patients with sIBM was collected and the sequencing of 38 genes associated with hereditary inclusion body myopathy (IBM), myofibrillar myopathy, Emery–Dreifuss muscular dystrophy, distal myopathy, amyotrophic lateral sclerosis and dementia along with C9orf72 hexanucleotide repeat analysis was performed. No C9orf72 repeat expansions were identified, however; 27 rare (minor allele frequency <1%) missense coding variants in several other genes were identified. One patient carried a p.R95C missense mutation in VCP and another carried a previously reported p.I27V missense mutation in VCP. Mutations in VCP cause IBM associated with Paget’s disease of the bone (PDB) and fronto-temporal dementia (IBMPFD). Neither patient had a family history of weakness or manifested other symptoms reported with VCP mutations such as PDB or dementia. In vitro analysis of these VCP variants found that they both disrupted autophagy similar to other pathogenic mutations. Although no clear genetic etiology has been implicated in sIBM pathogenesis, our study suggests that genetic evaluation in sIBM may be clinically meaningful and lend insight into its pathomechanism.

Sporadic inclusion body myositis: clinical, pathological, and genetic analysis of eight Polish patients

“…We detected no TARDBP mutation associated with IBM, which is consistent with Qian Gang et al's study (Qian Gang et al, 2014) [9]. We did not detect pathogenic hexanucleotide expansion in C9ORF72, which is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with TDP-43 inclusions (Weihl et al, 2015) [18]. Other possible genes associated with the disease may be HNRNPA1 and HNRNPA2B1 [16].…”

Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the C9orf72 expansion mutation

“…In the present study, we have found the missense p.I27V variant in a patient with a definitive diagnosis of lower MND with accompanying argyrophilic grains and mild AD-pathology, which may justify the clinical bvFTD syndrome as no classical FTLD pattern was observed. This mutation has been reported in a case with sporadic, isolated inclusion body myositis,23 a case with a progressive speech disturbance with no evidence of myopathy and a patient with a typical bvFTD 22. Thus, the VCP gene might have pleiotropic effects and a particular mutation in VCP can give rise to different phenotypes.…”

Sporadic inclusion body myositis: A review of recent clinical advances and current approaches to diagnosis and treatment

“…A recent Japanese study which screened for mutations in known hIBM and myofibrillar myopathy genes in a group of 21 patients with a diagnosis of inclusion body myositis did not find any mutations in VCP or GNE, but three patients had a mutation in MYHC2A which causes hIBM-3 (Cai et al, 2012). In another study of 79 IBM patients, pathogenic mutations in VCP were found in two patients who met the diagnostic criteria for IBM (Weihl et al, 2015). These findings emphasize the importance of defining stricter clinical and laboratory criteria for the diagnosis of sporadic inclusion body myositis and differentiation from hIBM.…”