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