title: Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia.
abstract: OBJECTIVE
  Cerebellar ataxias are a diverse collection of neurologic disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established.
  
  
  OBJECTIVE
  To investigate the contribution of genetic disease in a population of patients with predominantly adult- and sporadic-onset cerebellar ataxia.
  
  
  METHODS
  We examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia.
  
  
  METHODS
  Next-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation.
  
  
  RESULTS
  We identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias.
  
  
  CONCLUSIONS
  This study demonstrated that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high-yield test, providing a definitive diagnosis in more than one-fifth of patients and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Therefore, clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia.
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles.
authors.forename: Brent L
authors.initials: BL
authors.lastname: Fogel
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles3UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California at Los Angeles.
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles3UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California at Los Angeles.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Deignan
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles3UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California at Los Angeles.
authors.forename: Samuel P
authors.initials: SP
authors.lastname: Strom
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles3UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California at Los Angeles.
authors.forename: Sibel
authors.initials: S
authors.lastname: Kantarci
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles.
authors.forename: Xizhe
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles3UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California at Los Angeles.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Quintero-Rivera
authors.affiliation: UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California at Los Angeles4Department of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles5Department of Pediatrics, David Geffen School of.
authors.forename: Eric
authors.initials: E
authors.lastname: Vilain
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles3UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California at Los Angeles4Department of Human Genetics.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Grody
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles.
authors.forename: Susan
authors.initials: S
authors.lastname: Perlman
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles4Department of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles2Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles3UCLA Clin.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002524:Cerebellar Ataxia / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D017422:Sequence Analysis, DNA; D055815:Young Adult