Mutations in valosin‐containing protein (VCP), an ATPase involved in protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males and 113 females) from 36 families carrying 15 different VCP mutations. We analyzed the correlation between the different mutations and prevalence, age of onset and severity of myopathy, Paget's disease of bone (PDB), and frontotemporal dementia (FTD), and other comorbidities. Myopathy, PDB and FTD was present in 90%, 42% and 30% of the patients, respectively, beginning at an average age of 43, 41, and 56 years, respectively. Approximately 9% of patients with VCP mutations had an amyotrophic lateral sclerosis (ALS) phenotype, 4% had been diagnosed with Parkinson's disease (PD), and 2% had been diagnosed with Alzheimer's disease (AD). Large interfamilial and intrafamilial variation made establishing correlations difficult. We did not find a correlation between the mutation type and the incidence of any of the clinical features associated with VCP disease, except for the absence of PDB with the R159C mutation in our cohort and R159C having a later age of onset of myopathy compared with other molecular subtypes.

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Published in Clinical Genetics, v. 93, issue 1, p. 119-125.

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

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This is the peer reviewed version of the following article: Al‐Obeidi, E., Al‐Tahan, S., Surampalli, A., Goyal, N., Wang, A. K., Hermann, A., ... Kimonis, V. (2018). Genotype‐phenotype study in patients with valosin‐containing protein mutations associated with multisystem proteinopathy. Clinical Genetics, 93(1), 119-125, which has been published in final form at https://doi.org/10.1111/cge.13095. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

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Funding for these studies is from the National Institute of Health: Grant AR050236 (VK) and the UC Irvine ICTS (Institute of Clinical Translational Science)