Pathogenicity Classification of TARDBP Variants of Uncertain Significance: An Integrative Clinical Characterization...

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease often caused by mutations in the TAR DNA binding protein (TARDBP) gene.
• Mutant TDP-43 protein aggregates and mislocalizes, contributing to disease through gain-of-toxicity and loss-of-function mechanisms.
• In vitro functional assays are crucial for classifying the pathogenicity of TARDBP variants.

Purpose of the Study:

• To functionally classify 28 TARDBP variants of uncertain significance (VUS) using in vitro assays.
• To correlate TARDBP variant pathogenicity with clinical characteristics in ALS patients.
• To evaluate patient-derived fibroblasts as a model for variant assessment.

Main Methods:

• In vitro functional assays were used to assess the pathogenicity of 28 TARDBP VUS.
• Classification of variants followed American College of Medical Genetics (ACMG) and ClinGen SVI guidelines.
• Clinical data from 35 ALS patients with 12 TARDBP variants were summarized.

Main Results:

• Twenty-two of the 28 VUS were functionally abnormal.
• Twelve VUS were classified as likely pathogenic (LP) variants.
• Pathogenic variants were mainly in the C-terminal domain; exon 6 variants correlated with earlier onset.

Conclusions:

• Functional assays effectively classify TARDBP VUS pathogenicity, aiding ALS diagnosis and research.
• The study expands the known spectrum of pathogenic TARDBP mutations.
• Findings support the use of patient-derived fibroblasts and provide a basis for developing TARDBP-targeted ALS therapies.