title: Partially methylated alleles, microdeletion, and tissue mosaicism in a fragile X male with tremor and ataxia at 30 years of age: A case report.
abstract: CGG repeat expansion >200 within FMR1, termed full mutation (FM), has been associated with promoter methylation, consequent silencing of gene expression and fragile X syndrome (FXS)-a common cause of intellectual disability and co-morbid autism. Unmethylated premutation (55-199 repeats) and FM alleles have been associated with fragile X related tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder. Here we present a 33-year-old male with FXS, with white matter changes and progressive deterioration in gait with cerebellar signs consistent with probable FXTAS; there was no evidence of any other cerebellar pathology. We show that he has tissue mosaicism in blood, saliva, and buccal samples for the size and methylation of his expanded alleles and a de novo, unmethylated microdeletion. This microdeletion involves a ∼80 bp sequence in the FMR1 promoter as well as complete loss of the CGG repeat in a proportion of cells. Despite FMR1 mRNA levels in blood within the normal range, the methylation and CGG sizing results are consistent with the diagnosis of concurrent FXS and probable FXTAS. The demonstrated presence of unmethylated FM alleles would explain the manifestation of milder than expected cognitive and behavioral impairments and early onset of cerebellar ataxia. Our case suggests that individuals with FXS, who manifest symptoms of FXTAS, may benefit from more detailed laboratory testing. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Neurology, Gosford Hospital, Gosford, New South Wales, Australia.|Institute of Neurology, University College London, London, United Kingdom.
authors.forename: Yun Tae
authors.initials: YT
authors.lastname: Hwang
authors.affiliation: Cyto-Molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.|Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.|Molecular and Cytogenetics Laboratory, INTA University of Chile, Santiago, Chile.
authors.forename: Solange Mabel
authors.initials: SM
authors.lastname: Aliaga
authors.affiliation: Cyto-Molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.|Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Marta
authors.initials: M
authors.lastname: Arpone
authors.affiliation: Cyto-Molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Francis
authors.affiliation: Cyto-Molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Molecular Genetics Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Belinda
authors.initials: B
authors.lastname: Chong
authors.affiliation: Cyto-Molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.|Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Howard Robert
authors.initials: HR
authors.lastname: Slater
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, Australia.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Rogers
authors.affiliation: Department of Psychology, Royal Children's Hospital, Melbourne, Victoria, Australia.|Melbourne School of Psychological Sciences, University of Melbourne, Parkville, Melbourne, Australia.|Child Neuropsychology, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Lesley
authors.initials: L
authors.lastname: Bretherton
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, Australia.|Faculty of Medicine, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hunter
authors.affiliation: Department of Neurology, Gosford Hospital, Gosford, New South Wales, Australia.|Westmead Millennium Institute, University of Sydney, Westmead, New South Wales, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Heard
authors.affiliation: Cyto-Molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: David Eugeny
authors.initials: DE
authors.lastname: Godler
mesh_terms: D000328:Adult; D000483:Alleles; D001259:Ataxia / Q000175:diagnosis* / Q000235:genetics*; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000175:diagnosis* / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009030:Mosaicism; D009483:Neuropsychological Tests; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D017384:Sequence Deletion; D014202:Tremor / Q000175:diagnosis* / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; C497683:FMR1 protein, human
keywords: Fragile X syndrome; cerebellar ataxia; fragile X related tremor/ataxia syndrome; mental retardation; methylation; molecular biology; mosaicism; tremor