2025 American Academy of Neurology Abstract Website

Marijne Vandebergh¹, Eliana Marisa Ramos², Daniel Geschwind³, Saira Mirza⁴, Mario Masellis⁵, Ekaterina Rogaeva⁶, Lucy Chisman-Russell⁷, Jonathan Rohrer⁷, Hilary Heuer⁸, Leah Forsberg⁹, Adam Boxer⁸, Howard Rosen⁸, Bradley Boeve¹⁰, Rosa Rademakers¹¹
¹VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium, ²Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, USA, ³Institution for Precision Health, Departments of Neurology, Psychiatry and Human Genetics at David Geffen School of Medicine, University of California, Los Angeles, USA, ⁴L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Canada, ⁵L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Canada; Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre and the University of Toronto, Toronto, Canada, ⁶Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, Toronto, Canada, ⁷Department of Neurodegenerative Disease, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK, ⁸Department of Neurology, Memory and Aging Center, University of California, San Francisco Weill Institute for Neurosciences, San Francisco, USA, ⁹Department of Psychiatry and Psychology, ¹⁰Department of Neurology, Mayo Clinic, Rochester, USA, ¹¹VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Department of Neuroscience, Mayo Clinic, Jacksonville, USA

Objective:

Through characterization of the TMEM106B haplotype in large well-characterized cohorts of GRN pathogenic variant carriers, we aim to provide support for implementation of TMEM106B genetic testing in GRN pathogenic variant carriers in clinical testing.

Background:

Clinical genetic testing has been focused on autosomal dominant risk-increasing mutations rather than on genetic modifiers of disease. While TMEM106B has been shown to modify disease penetrance in GRN pathogenic variant carriers, genotyping of TMEM106B in GRN pathogenic variant carriers is currently not conducted in a clinical setting, not even in the event of a positive genetic test result for GRN in an asymptomatic individual.

Design/Methods:

Systematic genotype screens for TMEM106B haplotype in well-characterized cohorts, including cohorts from the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) consortium and the Genetic FTD Initiative (GENFI), are conducted.

Results:

Our preliminary data indicate a lower proportion of individuals homozygous for the protective TMEM106B haplotype in GRN carriers compared to individuals with a C9orf72 repeat expansion, MAPT pathogenic variant or non-mutation carriers. The majority of GRN carriers homozygous for the protective TMEM106B haplotype are asymptomatic. Importantly, some are still healthy despite relatively old age (> 70y). In those that are symptomatic, we have identified a case with a CSF1R mutation on top of the GRN mutation with a Parkinson-like phenotype. Whole genome sequencing is currently ongoing to further investigate other genetic causes of disease in symptomatic GRN carriers homozygous for the protective TMEM106B haplotype.

Conclusions:

Through investigation of TMEM106B haplotypes in GRN carriers we show that individuals with a GRN variant and homozygous for the protective haplotype are still healthy despite relatively old age, and that the disease in those affected might be caused by other genetic factors. Screening for TMEM106B in a clinical setting has important implications for genetic counselling and clinical trial inclusion criteria for GRN carriers.