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


METHODS
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.


METHODS
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.
Department of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195, USA.
Ying-Zhang
YZ
Chen
Mark M
MM
Matsushita
Peggy
P
Robertson
Mark
M
Rieder
Santhosh
S
Girirajan
Francesca
F
Antonacci
Hillary
H
Lipe
Evan E
EE
Eichler
Deborah A
DA
Nickerson
Thomas D
TD
Bird
Wendy H
WH
Raskind
D000262:Adenylyl Cyclases / Q000235:genetics*; D004252:DNA Mutational Analysis; D020821:Dystonic Disorders / Q000150:complications* / Q000235:genetics*; D059472:Exome; D005155:Facial Nerve Diseases / Q000150:complications* / Q000235:genetics*; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V