Autosomal Dominant Familial Dyskinesia and Facial Myokymia

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.2176GϾA) 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.

Gain‐of‐function ADCY5 mutations in familial dyskinesia with facial myokymia

“…Even with extensive clinical evaluation, it can be difficult to recognize features that suggest a specific diagnostic category. In ID1 and UW1, the perioral and periorbital movements, a prominent feature of FDFM, 1,6 had not been recognized as significant and other features differed from the one reported family. By themselves, the more prominent chorea and dystonia do not define a single disorder.…”

“…For ID1, 5 variants in 3 genes survived the filtration process and were corroborated by whole genome sequencing: a de novo missense variant in ADCY5 (c.1252C>T, p.R418W), a de novo missense variant (c.5645A>G, p.N1882S) and a maternally inherited mis-sense variant in DOCK3 (c.2557C>T, p.R853C), and 2 inherited heterozygous missense variants in FAT4 (paternal: c.524G>T, p.R175L; maternal: c.4000G>A, p.V1334M). We recently reported a mutation in ADCY5 as likely causative in a family with FDFM, an autosomal dominant movement disorder 1 (Supplementary Video). Although hypotonia was not seen in patients with FDFM and the facial movements were not initially recognized as significant in ID1, the ADCY5 variant was the strongest candidate given the clinical overlap.…”

“…1 Linkage analysis in a single family with 10 affected individuals in 3 generations had confined the locus to a 72.5Mb region on chromosome 3p21–3q21. Only 1 of the 5 variants in this region in the exome of 1 affected individual (c.2176G>A, p.A726T in ADCY5 ) was highly conserved, predicted to be pathogenic, and cosegregated perfectly with disease status.…”

“…4 We hypothesized that the adventitious movements in FDFM resulted from a gain-of-function effect of the mutation in ADCY5 . 1 This hypothesis was based on the phenotype of mice deficient in Adcy5 that develop parkinsonianlike motor dysfunction 5 —in some ways the opposite of what is observed in the family with FDFM. Despite 2 earlier publications that provided detailed phenotypic descriptions, 6,7 at that time no other families with a diagnosis of FDFM were identified in which to substantiate the role of ADCY5 .…”

Dysregulation of Corticostriatal Connectivity in Huntington’s Disease: A Role for Dopamine Modulation

“…3). Interestingly, increased AC activity has been found in other motor complications such as L-DOPA-induced dyskinesia [176, 177, 193, 194], autosomal dominant familiar dyskinesia, and myokymia [195]. …”