Abstract | 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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Authors | Ying-Zhang Chen, Mark M Matsushita, Peggy Robertson, Mark Rieder, Santhosh Girirajan, Francesca Antonacci, Hillary Lipe, Evan E Eichler, Deborah A Nickerson, Thomas D Bird, Wendy H Raskind |
Journal | Archives of neurology
(Arch Neurol)
Vol. 69
Issue 5
Pg. 630-5
(May 2012)
ISSN: 1538-3687 [Electronic] United States |
PMID | 22782511
(Publication Type: Case Reports, Journal Article, 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.)
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Chemical References |
- Adenylyl Cyclases
- adenylyl cyclase type V
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Topics |
- Adenylyl Cyclases
(genetics)
- DNA Mutational Analysis
- Dystonic Disorders
(complications, genetics)
- Exome
- Facial Nerve Diseases
(complications, genetics)
- Family Health
- Female
- Genetic Linkage
- Germany
- Humans
- Male
- Middle Aged
- Mutation, Missense
(genetics)
- Polymorphism, Single Nucleotide
(genetics)
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