title: ADCY5-related dyskinesia presenting as familial myoclonus-dystonia.
abstract: We describe a family with an autosomal dominant familial dyskinesia resembling myoclonus-dystonia associated with a novel missense mutation in ADCY5, found through whole-exome sequencing. A tiered analytical approach was used to analyse whole-exome sequencing data from an affected grandmother-granddaughter pair. Whole-exome sequencing identified 18,000 shared variants, of which 46 were non-synonymous changes not present in a local cohort of control exomes (n = 422). Further filtering based on predicted splicing effect, minor allele frequency in the 1000 Genomes Project and on phylogenetic conservation yielded 13 candidate variants, of which the heterozygous missense mutation c.3086T>G, p. M1029R in ADCY5 most closely matched the observed phenotype. This report illustrates the utility of whole-exome sequencing in cases of undiagnosed movement disorders with clear autosomal dominant inheritance. Moreover, ADCY5 mutations should be considered in cases with apparent myoclonus-dystonia, particularly where SCGE mutations have been excluded. ADCY5-related dyskinesia may manifest variable expressivity within a single family, and affected individuals may be initially diagnosed with differing neurological phenotypes.
authors.affiliation: Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.|Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Level G, Mailpoint 627, Princess Anne Hospital, Coxford Road, Southampton, SO16 5YA, UK.
authors.forename: Andrew G L
authors.initials: AG
authors.lastname: Douglas
authors.affiliation: Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Gaia
authors.initials: G
authors.lastname: Andreoletti
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
authors.affiliation: Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Simon R
authors.initials: SR
authors.lastname: Hammans
authors.affiliation: Paediatric Neurology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Jaspal
authors.initials: J
authors.lastname: Singh
authors.affiliation: Paediatric Neurology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Whitney
authors.affiliation: Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ennis
authors.affiliation: Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Level G, Mailpoint 627, Princess Anne Hospital, Coxford Road, Southampton, SO16 5YA, UK. nicola.foulds@uhs.nhs.uk.
authors.forename: Nicola C
authors.initials: NC
authors.lastname: Foulds
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002675:Child, Preschool; D020820:Dyskinesias / Q000150:complications / Q000235:genetics*; D020821:Dystonic Disorders / Q000150:complications / Q000235:genetics*; D005190:Family; D005260:Female; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype
chemical_list: D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V
keywords: ADCY5; Exome sequencing; Familial dyskinesia; Myoclonus-dystonia