2026 Theses Master's

Examining the Clinical and Genetic Spectrum of TARDBP-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Hospes, Katrina; Harrington, Elizabeth; Mulhern, Maureen S.; Chan, Amanda K.; Harms, Matthew

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal heterogeneous neurodegenerative disorder that primarily affects motor neurons in the brain and spinal cord, resulting in progressive muscle weakness. Beyond motor neuron deterioration, ALS symptomology can involve cognitive impairment, including frontotemporal dementia (FTD). Up to 15% of ALS cases have an identifiable genetic cause, and 2-5% are caused by variants in TARDBP, a gene also implicated in FTD. TARDBP-related ALS/FTD is clinically diverse, with differences seen in age and site of onset, survival, and expressivity. Founder variants and genotype-phenotype correlations for TARDBP ALS/FTD have been cataloged, but a gap remains in the literature regarding this clinical and genetic spectrum.

Objective: Describe the clinical and genetic heterogeneity of TARDBP-related ALS/FTD.

Methods: A literature review was conducted to identify genotype and phenotype information on TARDBP variants in individuals with ALS/FTD, yielding 535 cases across 94 studies. A chart review of individuals and families with TARDBP ALS/FTD seen at the Eleanor and Lou Gehrig ALS Center at Columbia University Irving Medical Center (CUIMC) from January 2000 to June 2025 identified 49 cases. Demographic information, genetic variants, clinical characteristics, and family history data were collected and analyzed using descriptive statistics, t-tests, Kruskal-Wallis tests, chi-square analysis, and Kaplan-Meier survival curves with Cox-proportional hazards regression.

Results: Across 584 total cases, 82 potentially pathogenic TARDBP variants were identified, including three missense variants from the CUIMC cohort which, to the authors’ knowledge, have never been described clinically in the literature: c.208A>G (p.N70D), c.983C>T (p.A328V), and c.1129T>A (p.S377T). Seven recurrent TARDBP variants accounted for nearly 60% of cases from the CUIMC cohort and literature review cases: c.881G>T (p.G294V), c.883G>A (p.G295S), c.892G>A (p.G298S), c.943G>A (p.A315T), c.1009A>G (p.M337V), c.1144G>A (p.A382T), and c.1147A>G (p.I383V). Analysis of these variants revealed significant differences in age of onset, disease duration, site of onset, family history of ALS/FTD, and cognitive status. Individuals with the p.M337V variant had the youngest age of onset and the longest survival, whereas those with the p.G294V variant had the latest age of onset and shorter survival. The p.A315T variant was disproportionately associated with spinal onset. The p.A382T variant was more likely to be associated with FTD, and impaired cognitive status was often seen with p.G295S and p.I383V, but never reported in individuals with p.G298S or p.A315T variants. Data regarding asymptomatic and obligate carrier status were also collected from the CUIMC cohort. Seventeen TARDBP variants were identified among carriers over the age of 57, the median age of onset of CUIMC probands who reported a family history of carriers.

Conclusions: Genotype-phenotype correlations were observed among the recurrent TARDBP variants. The genotype status of asymptomatic and obligate carriers from the CUIMC cohort was also documented, supporting reduced penetrance among TARDBP variants. Taken together, this information provides important context when counseling TARDBP-positive individuals and families affected by ALS/FTD. Ultimately, these findings expand the clinical and genetic spectrums of TARDBP ALS/FTD, underscoring their importance as access to genetic testing increases and gene therapies emerge.