TARDBP variants in Taiwanese ALS patients: Genetic spectrum, clinical features, and founder effects

TARDBP is one of the most commonly implicated genes in amyotrophic lateral sclerosis (ALS). It encodes TAR DNA-binding protein 43 (TDP-43), a protein critical to ALS pathology, whose pathogenic variants disrupt its nuclear-cytoplasmic translocation, leading to aggregation. This study aimed to investigate the role of TARDBP variants in a Taiwanese ALS cohort.

We analyzed the coding regions of TARDBP using Sanger sequencing in 650 unrelated ALS patients recruited between 2000 and 2024. The cohort included 388 men and 262 women, with an average age of onset of 56 ± 13 years. Approximately 20 % presented with bulbar-onset ALS. Haplotype analysis was conducted using single nucleotide polymorphism and short tandem repeat markers flanking TARDBP.

Pathogenic TARDBP variants were identified in 17 probands and 11 of their relatives, with an average age of onset of 49.1 ± 10.3 years, 32 % of whom had bulbar-onset disease. Six probands carried the p.M337V variant, five had p.S375G, two had p.N378D, and one each carried p.G348C, p.G348V, p.G376D, or p.I383V. Haplotype analysis suggested a common founder for the p.S375G variant and most families with p.M337V. Asymptomatic carriers were also identified, suggesting incomplete penetrance.

Our study revealed that pathogenic TARDBP variants are a significant genetic contributor to ALS in Taiwan, associated with earlier disease onset but reduced penetrance. The recurrent M337V and p.S375G variants likely reflect a founder effect.