常染色体显性遗传家族性运动障碍and facial myokymia: single exome sequencing identifies a mutation in adenylyl cyclase 5.
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Chen YZ, Matsushita MM, Robertson P, Rieder M, Girirajan S, Antonacci F, Lipe H, Eichler EE, Nickerson DA, Bird TD, Raskind WH
常染色体显性遗传家族性运动障碍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.
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22782511 [View in PubMed]
- Abstract
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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.