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Chen Y, Matsushita MM, Robertson P, et al. Autosomal Dominant Familial Dyskinesia and Facial Myokymia: Single Exome Sequencing Identifies a Mutation in Adenylyl Cyclase 5. Arch Neurol. 2012;69(5):630–635. doi:https://doi.org/10.1001/archneurol.2012.54
Author Affiliations: Departments of Medicine (Medical Genetics) (Drs Chen, Bird, and Raskind and Mr Matsushita), Genome Sciences (Drs Robertson, Rieder, Girirajan, Antonacci, Eichler, and Nickerson), Neurology (Ms Lipe and Dr Bird), and Psychiatry and Behavioral Sciences (Dr Raskind), University of Washington, Seattle; Howard Hughes Medical Institute, Chevy Chase, Maryland (Dr Eichler); and Veterans Integrated Service Network 20 Mental Illness Research, Education, and Clinical Center, Department of Veterans Affairs, Seattle (Drs Bird and Raskind).
Background Familial dyskinesia with facial myokymia (FDFM) is an autosomal dominant disorder that is exacerbated by anxiety. In a 5-generation family of German ancestry, we previously mapped FDFM to chromosome band 3p21-3q21. The 72.5-Mb linkage region was too large for traditional positional mutation identification.
Objective To identify the gene responsible for FDFM by exome resequencing of a single affected individual.
Participants We performed whole exome sequencing in 1 affected individual and used a series of bioinformatic filters, including functional significance and presence in dbSNP or the 1000 Genomes Project, to reduce the number of candidate variants. Co-segregation analysis was performed in 15 additional individuals in 3 generations.
Main Outcome Measures Unique DNA variants in the linkage region that co-segregate with FDFM.
Results The exome contained 23 428 single-nucleotide variants, of which 9391 were missense, nonsense, or splice site alterations. The critical region contained 323 variants, 5 of which were not present in 1 of the sequence databases. Adenylyl cyclase 5 (ADCY5) was the only gene in which the variant (c.2176G>A) was co-transmitted perfectly with disease status and was not present in 3510 control white exomes. This residue is highly conserved, and the change is nonconservative and predicted to be damaging.
Conclusions ADCY5 is highly expressed in striatum. Mice deficient in Adcy5 develop a movement disorder that is worsened by stress. We conclude that FDFM likely results from a missense mutation in ADCY5. This study demonstrates the power of a single exome sequence combined with linkage information to identify causative genes for rare autosomal dominant mendelian diseases.
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