Valosin-Containing Protein-Related Disorders via the VCP Gene

Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD, OMIM 167320) is characterized by adult-onset proximal and distal muscle weakness, early-onset Paget disease of bone, and frontotemporal dementia (Kimonis et al. GeneReviews 2011). Muscle weakness resembles that seen in limb-girdle muscular dystrophy, and respiratory and cardiac involvement may occur later in the disease course. Serum CK is typically normal or mildly elevated, and EMG studies demonstrate myopathic changes (Kimonis et al. Genet Med 2:232-241, 2000). Symptoms of bone disease include pain of the spine and hip and enlargement and deformity of the long bones. Bone symptoms originate from focal abnormalities of increased bone turnover (Kimonis et al. Am J Med Genet 146A:745-757, 2008). Serum alkaline phosphatase levels are elevated as are urine pyridinoline and deoxypyridinoline concentrations. Early signs of frontotemporal dementia include social unawareness and disinhibition, expressive or receptive language dysfunction, and relative sparing of memory (Kimonis et al. GeneReviews 2011). IBMPFD is a progressive disease leading to disabling muscle and bone disease and inability to speak. An exome sequencing strategy revealed that familial amyotrophic lateral sclerosis with or without frontotemporal dementia (ALS14, OMIM 613954) results from variants in the VCP gene (Johnson et al. Neuron 68:857-864, 2010).

Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia is an autosomal dominant disorder with incomplete penetrance of the three clinical features (limb-girdle muscle weakness, Paget disease of bone, and frontotemporal dementia). Missense variants of the VCP gene (OMIM 601023) are the only known cause of IBMPFD, and substitution of the Arg155 residue was shown to be the predominant variant among North American patients (Watts et al. Nat Genet 36:377-381, 2004). ALS14 is also an autosomal dominant disorder.

Sensitivity should be high in patients meeting clinical criteria for all three symptoms of IBMPFD. In one study, 10 of 13 affected families had a variant involving Arg155 (Watts et al. Nat Genet 36:377-381, 2004). VCP variants are probably a rare cause of ALS. Screening of the VCP gene in 210 familial ALS cases and 78 autopsy-proven ALS cases identified 3 variants in 4 patients (Johnson et al. Neuron 68:857-864, 2010).

This test provides full coverage of all coding exons of the VCP gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.