One family, one gene and three phenotypes: A novel VCP (valosin-containing protein) mutation associated with myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and frontotemporal dementia

• VCP missense variants have been associated with variable phenotypes.
• Reported phenotypes include IBM, ALS and FTD.
• We report a novel VCP variant with intrafamilial phenotypic variability.
• This study expands the genotypic spectrum of VCP missense variants.

BackgroundVCP (valosin-containing protein gene) variants have been associated with peripheral and central neurodegenerative processes, including inclusion body myopathy (IBM), Paget disease of bone (PDB), frontotemporal dementia (FTD), and familial amyotrophic lateral sclerosis (ALS) type 14. The combination of IBM, PDB (IBMPFD1) can presented in one individual. However, the association of IBMPFD1 and ALS in the same family is rare.MethodsWe reported three individuals from a Brazilian kindred with intrafamilial phenotype variability. Whole exome sequencing (WES) of the proband was performed and revealed a novel VCP variant. VCP Sanger sequencing was performed in the proband and his family members to confirm WES finding and segregation. We performed a systematic review of the literature regarding the genotypic-phenotypic VCP correlations.ResultsEach individual presented with either myopathy with rimmed vacuoles, ALS, or FTD. There was no PDB. WES of the proband identified the heterozygous variant c.271A > T (p.Asn91Tyr) in the exon 3 of VCP. Sanger sequencing confirmed the segregation of this variant in an autosomal-dominant pattern.ConclusionThis study expands the genotypic spectrum of the missense mutations of the VCP gene with a novel p.Asn91Tyr variant found in a Brazilian family presenting with the unusual intrafamiliar association of myopathy with rimmed vacuoles, ALS and FTD.