ClinVar Genomic variation as it relates to human health

In 4 affected sibs of an Austrian family with autosomal dominant inclusion body myopathy and Paget disease but without dementia (IBMPFD1; 167320), Haubenberger et al. (2005) identified a heterozygous 688G-A transition in exon 5 of the VCP gene, resulting in an arg159-to-his (R159H) substitution. The mutation occurred in a highly conserved region close to the codon 155 hotspot described by Watts et al. (2004) and was not present in 384 control chromosomes. None of the 4 affected sibs demonstrated frontotemporal dementia even though all were over 60 years of age. Haubenberger et al. (2005) noted that only approximately 30% of patients with VCP mutations develop dementia, illustrating phenotypic variability. In a follow-up of this family, van der Zee et al. (2009) noted that 1 patient had developed dementia at age 64. Van der Zee et al. (2009) also identified the R159H mutation in affected members of 2 unrelated Belgian families. In 1 family, patients presented with frontotemporal lobar degeneration only, whereas in the other family, patients developed frontotemporal lobar degeneration, Paget disease of the bone, or both without signs of inclusion body myopathy for any of the mutation carriers. Haplotype analysis showed that the 2 families and the Austrian family reported by Haubenberger et al. (2005) were unrelated. Autopsy data of 3 patients from the 2 Belgian families showed frontotemporal lobar degeneration with numerous ubiquitin-immunoreactive, intranuclear inclusions and dystrophic neurites staining positive for TDP43 (TARDBP; 605078) protein. Van der Zee et al. (2009) commented on the high degree of clinical heterogeneity and incomplete penetrance of the disorder in different families carrying the same mutation. De Ridder et al. (2020) reported a 36-year-old Belgian man with onset of IBMPFD1 at age 29 years who carried a homozygous R159H mutation in the VCP gene. His 63-year-old father, who carried the mutation in heterozygous state, had a similar myopathic phenotype with later onset at age 58. His 60-year-old mother, who was also heterozygous for the mutation, was clinically unaffected. The proband presented with progressive proximal muscle weakness with possible neurogenic features and high serum creatine kinase; an asymptomatic Paget bone lesion was later identified. Neither patient had dementia. Functional studies of the variant were not performed, but proteomic analysis of skeletal muscle from the proband and his father, as well as from 3 additional patients with VCP-related myopathy, showed changes in upstream regulators involved in myogenesis, muscle regeneration, oxidative stress, endoplasmic reticulum stress, stress granules, and the unfolded protein response. (less)