title: Genomic studies in fragile X premutation carriers.
abstract: BACKGROUND
  The FMR1 premutation is defined as having 55 to 200 CGG repeats in the 5' untranslated region of the fragile X mental retardation 1 gene (FMR1). The clinical involvement has been well characterized for fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). The behavior/psychiatric and other neurological manifestations remain to be specified as well as the molecular mechanisms that will explain the phenotypic variability observed in individuals with the FMR1 premutation.
  
  
  METHODS
  Here we describe a small pilot study of copy number variants (CNVs) in 56 participants with a premutation ranging from 55 to 192 repeats. The participants were divided into four different clinical groups for the analysis: those with behavioral problems but no autism spectrum disorder (ASD); those with ASD but without neurological problems; those with ASD and neurological problems including seizures; and those with neurological problems without ASD.
  
  
  RESULTS
  We found 12 rare CNVs (eight duplications and four deletions) in 11 cases (19.6%) that were not found in approximately 8,000 controls. Three of them were at 10q26 and two at Xp22.3, with small areas of overlap. The CNVs were more commonly identified in individuals with neurological involvement and ASD.
  
  
  CONCLUSIONS
  The frequencies were not statistically significant across the groups. There were no significant differences in the psychometric and behavior scores among all groups. Further studies are necessary to determine the frequency of second genetic hits in individuals with the FMR1 premutation; however, these preliminary results suggest that genomic studies can be useful in understanding the molecular etiology of clinical involvement in premutation carriers with ASD and neurological involvement.
authors.affiliation: MIND Institute, UC Davis Medical Center, Sacramento, 2825 50th Street, California, CA 95817, USA ; Department of Pediatrics, UC Davis Medical Center, Sacramento, CA, USA.
authors.forename: Reymundo
authors.initials: R
authors.lastname: Lozano
authors.affiliation: MIND Institute, UC Davis Medical Center, Sacramento, 2825 50th Street, California, CA 95817, USA ; Department of Pediatrics, UC Davis Medical Center, Sacramento, CA, USA.
authors.forename: Randi J
authors.initials: RJ
authors.lastname: Hagerman
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Duyzend
authors.affiliation: Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Dejan B
authors.initials: DB
authors.lastname: Budimirovic
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA ; Howard Hughes Medical Institute, Seattle, WA, USA.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.affiliation: MIND Institute, UC Davis Medical Center, Sacramento, 2825 50th Street, California, CA 95817, USA ; Department of Biochemistry and Molecular Medicine, UC Davis Medical Center, Sacramento, CA, USA.
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
keywords: ASD; Autism; FMR1 gene; Neurodevelopmental disorders; Neurological disorders; Premutation; Second hit