Mild Neurological Phenotype Associated with Hypomorphic Variants in the Ataxia‐Telangiectasia Mutated Gene

Abstract

Background Ataxia‐telangiectasia (A‐T) is a progressive multisystemic neurodegenerative disease. The phenotypic spectrum includes conditions (variant A‐T) with mild, late‐onset, and atypical clinical presentations characterized by the prevalence of dyskinetic rather than ataxic features. Cases We describe the clinical presentations of 3 siblings with early‐onset truncal ataxia without obvious neurological deterioration or biological markers of classic A‐T phenotype. We performed functional and genetic evaluation of 3 siblings with very mild neurological phenotype. Genetic evaluation with a next‐generation sequencing panel for genes causative of cerebellar ataxia detected 2 known ATM gene variants, missense c.9023G>A p.(Arg3008His), and leaky splicing c.1066‐6T>G variants. Functional studies showed mildly reduced ATM expression and residual kinase activity in the probands compared with healthy controls. Conclusions These results suggest the importance of investigating ATM variants even in the presence of clinical and biological atypical cases to ensure specific therapeutic regimens and oncological surveillance in these patients.