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.

Keywords: ADCY5; Exome sequencing; Familial dyskinesia; Myoclonus-dystonia.

Fig. 1

a Pedigree of the family described in this case report. Affected individuals are shaded, all of whom have had molecular confirmation of the ADCY5 mutation except for individual II.3, who has not been assessed clinically but is said to have similar symptoms to individual II.2. The precise phenotypes of individuals in generation I are uncertain, relying on familial hear-say, and no medical records were available for review. Asterisks indicate individuals that underwent WES (IV.1 and II.2). b Adenylyl cyclase (AC5) protein domains and locations of previously reported ADCY5 disease-causing mutations, including the novel p. M1029R variant observed in this family. The G-protein coupled receptor stimulates AC5 protein activity. AC5 contains two six-helical transmembrane domains (TM1 and TM2) and two cytoplasmic catalytic domains (C1 and C2). The two cytosolic domains form a pocket to convert ATP to cAMP. The ADCY5 mutation segregating in our family causes a T > G change at nucleotide position 3086 in exon 18, leading to a methionine to arginine change at codon 1029. The variant occurs in the second cytoplasmic loop [2]