Autosomal dominant familial dyskinesia and facial myokymia: single exome sequencing identifies a mutation in adenylyl cyclase 5

Arch Neurol. 2012 May;69(5):630-5. doi: 10.1001/archneurol.2012.54.


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.

Publication types

  • Case Reports
  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenylyl Cyclases / genetics*
  • DNA Mutational Analysis
  • Dystonic Disorders / complications*
  • Dystonic Disorders / genetics*
  • Exome
  • Facial Nerve Diseases / complications*
  • Facial Nerve Diseases / genetics*
  • Family Health
  • Female
  • Genetic Linkage
  • Germany
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense / genetics*
  • Polymorphism, Single Nucleotide / genetics


  • Adenylyl Cyclases
  • adenylyl cyclase type V