Intrafamilial Variability in Ataxia-Telangiectasia: A Case Report of Three Siblings with Identical ATM Mutations

Ataxia-telangiectasia (A-T) is a rare, autosomal recessive neurodegenerative disorder caused by pathogenic variants in the ATM (ataxia-telangiectasia mutated) gene, located on chromosome 11q22–23. The ATM protein is a serine/threonine kinase essential for the detection of DNA double-strand breaks and activation of cell-cycle checkpoints. Classic A-T typically manifests in early childhood with progressive cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, radiosensitivity, and a high predisposition to malignancy.[1]

We describe a non-consanguineous family with three siblings affected by ataxia-telangiectasia (A-T) due to identical compound heterozygous pathogenic variants in the ATM gene: c.72+2T>C (splice donor mutation) and c.6100C>T (p. Arg2034Ter, nonsense mutation). Despite sharing the same genotype, the siblings exhibited marked variability in age of onset and clinical progression, ranging from early-childhood gait instability to late-onset regression of previously normal motor skills. All affected siblings had elevated serum alpha-fetoprotein (AFP) and cerebellar signs, but differed in the timing of telangiectasia appearance and severity of motor impairment. This report highlights the role of genetic background and possible modifier factors in the phenotypic expression of A-T.