Abstract Details

Title The road towards implementation of TMEM106B genetic testing in clinical practice in progranulin pathogenic variant carriers

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P3 - Poster Session 3 (11:45 AM-12:45 PM)

Poster/Presentation
Number 3-020

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.

Authors/Disclosures
Marijne Vandebergh, PhD (VIB-UAntwerp Center for Molecular Neurology) PRESENTER	Dr. Vandebergh has received research support from the Queen Elisabeth Medical Foundation for Neurosciences. Dr. Vandebergh has received research support from CReATe Consortium and American Brain Foundation - in collaboration with AAN .
Eliana Marisa Ramos, PhD	The institution of Dr. Ramos has received research support from NIH.
Daniel H. Geschwind, MD, PhD (UCLA)	Dr. Geschwind has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Ovid Therapeutics, Inc.. Dr. Geschwind has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for AcuraStem, Inc.. Dr. Geschwind has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Axial Biotherapeutics, Inc.. Dr. Geschwind has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Falcon Computing. Dr. Geschwind has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier-Biological Psychiatry. Dr. Geschwind has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for NYAS. Dr. Geschwind has received personal compensation in the range of $50,000-$99,999 for serving as an Expert Witness for Covington& Burling LLP. Dr. Geschwind has stock in none related to talk. The institution of Dr. Geschwind has received research support from CurePSP. The institution of Dr. Geschwind has received research support from NINDS. The institution of Dr. Geschwind has received research support from Rainwater Charitable Foundation. The institution of Dr. Geschwind has received research support from NIMH. The institution of Dr. Geschwind has received research support from NINDS. The institution of Dr. Geschwind has received research support from NIH. The institution of Dr. Geschwind has received research support from The Simons Foundation. The institution of Dr. Geschwind has received research support from NIH/NIMH. The institution of Dr. Geschwind has received research support from Adelson Medical Research Foundation. The institution of Dr. Geschwind has received research support from NINDS. The institution of Dr. Geschwind has received research support from NIMH. The institution of Dr. Geschwind has received research support from NINDS/NIA. The institution of Dr. Geschwind has received research support from NIH/NIMH. The institution of Dr. Geschwind has received research support from Adelson Medical Research Foundation. The institution of Dr. Geschwind has received research support from NIH/NINDS. The institution of Dr. Geschwind has received research support from NIH/NIMH. The institution of Dr. Geschwind has received research support from NIH/NIMH. The institution of Dr. Geschwind has received research support from Adelson Medical Research Foundation. The institution of Dr. Geschwind has received research support from U of Virginia and NIH/NIMH. The institution of Dr. Geschwind has received research support from NIH. The institution of Dr. Geschwind has received research support from NIH/NHGRI. The institution of Dr. Geschwind has received research support from NIH/NIMH. Dr. Geschwind has received intellectual property interests from a discovery or technology relating to health care. Dr. Geschwind has received intellectual property interests from a discovery or technology relating to health care. Dr. Geschwind has received intellectual property interests from a discovery or technology relating to health care. Dr. Geschwind has received intellectual property interests from a discovery or technology relating to health care.
Saira Mirza, MBBS, PhD	Dr. Mirza has nothing to disclose.
Mario Masellis, MD (Sunnybrook Health Sciences Centre)	Dr. Masellis has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Arkuda Therapeutics. Dr. Masellis has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Ionis. Dr. Masellis has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alector. Dr. Masellis has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Wave Life Sciences. The institution of Dr. Masellis has received research support from Canadian Institutes of Health Research. The institution of Dr. Masellis has received research support from Ontario Brain Institute. The institution of Dr. Masellis has received research support from Weston Brain Institute. The institution of Dr. Masellis has received research support from Washington University. The institution of Dr. Masellis has received research support from Alector. Dr. Masellis has received publishing royalties from a publication relating to health care.
Ekaterina Rogaeva, PhD	Dr. Rogaeva has nothing to disclose.
Lucy L. Russell, PhD	Dr. Russell has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Prevail Therapeutics.
Jonathan D. Rohrer (Dementia Research Centre)	Dr. Rohrer has nothing to disclose.
Hilary Heuer (UCSF)	Hilary Heuer has nothing to disclose.
Leah K. Forsberg, PhD (Mayo Clinic)	Ms. Forsberg has nothing to disclose.
Adam L. Boxer, MD, PhD (University of California, San Francisco)	An immediate family member of Dr. Boxer has received personal compensation for serving as an employee of Kaiser Permanente. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ono. Dr. Boxer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Oscotec. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Boxer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Arrowhead. Dr. Boxer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Neurocrine Biosciences. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Switch. Dr. Boxer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Arvinas. Dr. Boxer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Alector. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Boxer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Transposon. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen . Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Boxer has stock in Alector. Dr. Boxer has stock in Arvinas. Dr. Boxer has stock in Neurovanda. The institution of Dr. Boxer has received research support from Biogen. The institution of Dr. Boxer has received research support from Eisai. The institution of Dr. Boxer has received research support from Regeneron. The institution of Dr. Boxer has received research support from NIH. The institution of Dr. Boxer has received research support from Bluefield Project-5. Dr. Boxer has received research support from Rainwater Charitable Foundation. Dr. Boxer has received research support from GHR Foundation. Dr. Boxer has received intellectual property interests from a discovery or technology relating to health care.
Howard J. Rosen, MD (UCSF)	Dr. Rosen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly . Dr. Rosen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alector. The institution of Dr. Rosen has received research support from NIH. The institution of Dr. Rosen has received research support from State of CA. Dr. Rosen has a non-compensated relationship as a Consultant with Prevail Therapeutics that is relevant to AAN interests or activities. Dr. Rosen has a non-compensated relationship as a consultant with Alchemab that is relevant to AAN interests or activities.
Bradley F. Boeve, MD, FAAN (Mayo Clinic)	Dr. Boeve has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Rainwater Charitable Foundation. The institution of Dr. Boeve has received research support from Alector. The institution of Dr. Boeve has received research support from EIP Pharma. The institution of Dr. Boeve has received research support from Transposon. The institution of Dr. Boeve has received research support from Cognition Therapeutics. Dr. Boeve has received publishing royalties from a publication relating to health care.
Rosa Rademakers, PhD (Mayo Clinic Dept of Neuroscience)	Rosa Rademakers, PhD has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Mayo Clinic. Rosa Rademakers, PhD has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Arkuda Therapeutics. Rosa Rademakers, PhD has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Alzheimer Fondation. Rosa Rademakers, PhD has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Kisick Family Foundation (FTD grant program). The institution of Rosa Rademakers, PhD has received research support from NIH. The institution of Rosa Rademakers, PhD has received research support from DOD. The institution of Rosa Rademakers, PhD has received research support from Flanders Institute for Biotechnology (VIB). The institution of Rosa Rademakers, PhD has received research support from Flanders Funds for Scientific Research.

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