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'Essential Tremor' Phenotype in FMR1 Premutation/Gray Zone Sibling Series: Exploring Possible Genetic Modifiers.
Loesch, Danuta Z; Duffy, David L; Martin, Nicholas G; Tassone, Flora; Atkinson, Anna; Storey, Elsdon.
Afiliación
  • Loesch DZ; School of Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia.
  • Duffy DL; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
  • Martin NG; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
  • Tassone F; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA.
  • Atkinson A; M.I.N.D. Institute, University of California Davis Medical Center, Davis, CA, USA.
  • Storey E; School of Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia.
Twin Res Hum Genet ; 24(2): 95-102, 2021 04.
Article en En | MEDLINE | ID: mdl-33757613
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Temblor Esencial / Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil Límite: Female / Humans / Male País/Región como asunto: Oceania Idioma: En Revista: Twin Res Hum Genet Asunto de la revista: GENETICA MEDICA Año: 2021 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Temblor Esencial / Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil Límite: Female / Humans / Male País/Región como asunto: Oceania Idioma: En Revista: Twin Res Hum Genet Asunto de la revista: GENETICA MEDICA Año: 2021 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Reino Unido