A rare ATM variant in a Colombian family with chorea-ataxia syndrome: implications for an early diagnosis.

Ataxia-telangiectasia (ATX-ATM) is a rare multisystem disorder caused by pathogenic variants in the ataxia-telangiectasia mutated (ATM) gene. The classic phenotype is characterized by childhood-onset progressive cerebellar ataxia and movement disorders, accompanied by telangiectasias, primary immunodeficiency, chronic pulmonary disease, endocrine abnormalities, and increased sensitivity to ionizing radiation, as well as a markedly elevated risk of malignancy. In contrast, variant ATX-ATM is associated with a milder and more heterogeneous phenotype, in which cerebellar ataxia may be absent, while dystonia and axonal sensorimotor neuropathy are common; immune and respiratory function are typically preserved, although the risk of malignancy remains increased. We report a 39-year-old man presenting with progressive ataxia, chorea, and telangiectasias, with two siblings exhibiting a similar phenotype. Notably, one sibling developed diffuse gastric adenocarcinoma and cutaneous melanoma, whereas his sister died from ovarian and colon cancer. Whole-exome sequencing identified compound heterozygous variants in the ATM gene in the two affected siblings: a pathogenic splice-site variant, c.2921 + 1G > A, and a heterozygous missense variant of uncertain significance, c.8083G > A; p.(Gly2695Ser). Segregation analysis confirmed that these variants were in trans, supporting the identification of a rare ATM variant associated with ATX-ATM in this family. The diagnosis of variant ATX-ATM remains challenging because of its marked phenotypic heterogeneity. Nevertheless, early recognition is essential given the substantially increased risk of malignancy and the need for appropriate oncologic surveillance and genetic counseling. The identification and reporting of ATM variants contribute to improved genotype-phenotype correlations and broaden the current understanding of disease variability.