ADCY5-related dyskinesia presenting as familial myoclonus-dystonia

• Published in: Neurogenetics Vol. 18; no. 2; pp. 111 - 117
• Main Authors: Douglas, Andrew G. L., Andreoletti, Gaia, Talbot, Kevin, Hammans, Simon R., Singh, Jaspal, Whitney, Andrea, Ennis, Sarah, Foulds, Nicola C.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2017; Springer Nature B.V
• Subjects: Adenylyl Cyclases - genetics; Adolescent; Adult; Biomedical and Life Sciences; Biomedicine; Child, Preschool; Dyskinesias - complications; Dyskinesias - genetics; Dystonic Disorders - complications; Dystonic Disorders - genetics; Family; Female; Human Genetics; Humans; Middle Aged; Molecular Medicine; Mutation; Mutation, Missense; Neurological disorders; Neurosciences; Pedigree; Phenotype; Phylogenetics; Short Communication; Myoclonus-dystonia; Familial dyskinesia; Exome sequencing; ADCY5
• ISSN: 1364-6745; 1364-6753
• DOI: 10.1007/s10048-017-0510-z

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.