title: A novel ANO3 variant identified in a 53-year-old woman presenting with hyperkinetic dysarthria, blepharospasm, hyperkinesias, and complex motor tics.
abstract: BACKGROUND
  Cervical dystonias have a variable presentation and underlying etiology, but collectively represent the most common form of focal dystonia. There are a number of known genetic forms of dystonia (DYT1-27); however the heterogeneity of disease presentation does not always make it easy to categorize the disease by phenotype-genotype comparison.
  
  
  METHODS
  In this report, we describe a 53-year-old female who presented initially with hand tremor following a total hip arthroplasty. The patient developed a mixed hyperkinetic disorder consisting of chorea, dystonia affecting the upper extremities, dysarthria, and blepharospasm. Whole exome sequencing of the patient revealed a novel heterozygous missense variant (Chr11(GRCh38): g.26525644C > G; NM_031418.2(ANO3): c.702C > G; NP_113606.2. p.C234W) in exon 7 in the ANO3 gene.
  
  
  CONCLUSIONS
  ANO3 encodes anoctamin-3, a Ca+2-dependent phospholipid scramblase expressed in striatal-neurons, that has been implicated in autosomal dominant craniocervical dystonia (Dystonia-24, DYT24, MIM# 615034). To date, only a handful of cases of DYT-24 have been described in the literature. The complex clinical presentation of the patient described includes hyperkinesias, complex motor movements, and vocal tics, which have not been reported in other patients with DYT24. This report highlights the utility of using clinical whole exome sequencing in patients with complex neurological phenotypes that would not normally fit a classical presentation of a defined genetic disease.
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Jacksonville, FL, USA.|Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Blackburn
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Zimmermann
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Jacksonville, FL, USA.|Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Gass
authors.affiliation: Department of Clinical Genomics, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, 32224, USA.
authors.forename: Kimberly G
authors.initials: KG
authors.lastname: Harris
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.|Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Margot A
authors.initials: MA
authors.lastname: Cousin
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.|Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Boczek
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.|Department of Clinical Genomics, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, 32224, USA.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.|Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Klee
authors.affiliation: Department of Ophthalmology, Mayo Clinic, Jacksonville, FL, USA.|Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Brazis
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Van Gerpen
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Jacksonville, FL, USA. Atwal.Paldeep@mayo.edu.|Department of Clinical Genomics, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, 32224, USA. Atwal.Paldeep@mayo.edu.
authors.forename: Paldeep S
authors.initials: PS
authors.lastname: Atwal
mesh_terms: D000005:Abdomen / Q000000981:diagnostic imaging; D000595:Amino Acid Sequence; D000075368:Anoctamins; D001764:Blepharospasm / Q000150:complications / Q000235:genetics* / Q000473:pathology; D018118:Chloride Channels / Q000235:genetics*; D004401:Dysarthria / Q000150:complications / Q000235:genetics* / Q000473:pathology; D004421:Dystonia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D004594:Electrophysiology; D005091:Exons; D005260:Female; D006579:Heterozygote; D006801:Humans; D006948:Hyperkinesis / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D011110:Polymorphism, Genetic; D016415:Sequence Alignment; D020323:Tics / Q000150:complications / Q000235:genetics* / Q000473:pathology
chemical_list: C577591:ANO3 protein, human; D000075368:Anoctamins; D018118:Chloride Channels
keywords: ANO3; Anoctamin-3; Craniocervical dystonia; DYT24; Dystonia-24