'Essential Tremor' Phenotype in FMR1 Premutation/Gray Zone Sibling Series: Exploring Possible Genetic Modifiers

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Fragile X-associated tremor/ataxia syndrome (FXTAS) is linked to CGG repeat expansions in the FMR1 gene.
• FXTAS presents with kinetic tremor, gait ataxia, cognitive decline, and white matter lesions.
• The role of polygenic factors in modifying FXTAS phenotypes is not well understood.

Purpose of the Study:

• To investigate polygenic effects that may modify the spectrum of phenotypes in FXTAS.
• To explore the genetic underpinnings of neurological symptoms in FMR1 small expansion carriers.

Main Methods:

• Genomewide association study (SNP genotyping) was performed on siblings carrying FMR1 gray zone (GZ) or premutation (PM) alleles.
• Nonparametric linkage analysis and calculation of Parkinson's disease (PD) polygenic risk scores (PRSs) were conducted.
• Neurological and cognitive assessments, including motor scales and cognitive tests, were administered.

Main Results:

• All siblings exhibited kinetic tremor, but showed minimal gait ataxia and few white matter lesions.
• Cognitive functions remained unaffected in the studied siblings.
• Suggestive linkage evidence was found on chromosome 10, and PD PRS indicated a moderate genetic risk for Parkinson's disease.

Conclusions:

• Genomic risk loci associated with Parkinson's disease may modify the neurological phenotype in FMR1 small expansion carriers.
• This polygenic influence could contribute to an oligosymptomatic kinetic tremor, resembling FXTAS spectrum or essential tremor.