Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
33757613
TITLE
'Essential Tremor' Phenotype in FMR1 Premutation/Gray Zone Sibling Series: Exploring Possible Genetic Modifiers.
ABSTRACT
Fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in carriers of fragile X mental retardation 1 (FMR1) X-linked small CGG expansion (gray zone [GZ] and premutation [PM]) alleles, containing 41-200 repeats. Major features comprise kinetic tremor, gait ataxia, cognitive decline and cerebellar peduncular white matter lesions, but atypical/incomplete FXTAS may occur. We explored the possibility of polygenic effects modifying the FXTAS spectrum phenotypes. We used three motor scales and selected cognitive tests in a series of three males and three females from a single sibship carrying PM or GZ alleles (44 to 75 repeats). The molecular profiles from these siblings were determined by genomewide association study with single-nucleotide polymorphism (SNP) genotyping by Illumina Global Screening Array. Nonparametric linkage analysis was applied and Parkinson's disease (PD) polygenic risk scores (PRSs) were calculated for all the siblings, based on 107 known risk variants. All male and female siblings manifested similar kinetic tremor phenotypes. In contrast to FXTAS, they showed negligible gait ataxia, and few white matter lesions on MRI. Cognitive functioning was unaffected. Suggestive evidence of linkage to a broad region of the short arm of chromosome 10 was obtained, and median PD PRS for the sibship fell within the top 30% of a sample of over 500,000 UK and Australian controls. The genomewide study results are suggestive of modifying effects of genetic risk loci linked to PD, on the neurological phenotype of FMR1-CGG small expansion carriers, resulting in an oligosymptomatic kinetic tremor seen in FXTAS spectrum, but also consistent with essential tremor.
DATE PUBLISHED
2021 Mar 24
HISTORY
PUBSTATUS PUBSTATUSDATE
entrez 2021/03/24 05:49
pubmed 2021/03/25 06:00
medline 2021/03/25 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Loesch DZ Loesch Danuta Z DZ School of Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia.
Duffy DL Duffy David L DL Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Martin NG Martin Nicholas G NG Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Tassone F Tassone Flora F M.I.N.D. Institute, University of California Davis Medical Center, Davis, CA, USA.
Atkinson A Atkinson Anna A School of Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia.
Storey E Storey Elsdon E Department of Medicine (Neuroscience), Monash University, Melbourne, Victoria, Australia.
INVESTIGATORS
JOURNAL
VOLUME:
ISSUE:
TITLE: Twin research and human genetics : the official journal of the International Society for Twin Studies
ISOABBREVIATION: Twin Res Hum Genet
YEAR: 2021
MONTH: Mar
DAY: 24
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1832-4274
ISSNTYPE: Print
MEDLINE JOURNAL
MEDLINETA: Twin Res Hum Genet
COUNTRY: England
ISSNLINKING: 1832-4274
NLMUNIQUEID: 101244624
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
COMMENTS AND CORRECTIONS
GRANTS
GENERAL NOTE
KEYWORDS
KEYWORD
FMR1 premutation/gray zone
FXTAS spectrum
genetic modifiers
isolated tremor in sibship
polygenic PD scores
MESH HEADINGS
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's