Genetic Spectrum of ATM Founder Mutations and Malignancy in Ataxia-Telangiectasia

Background Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by pathogenic variants in the ATM gene and characterized by genomic instability, immunodeficiency, and a markedly increased risk of cancer. In Costa Rica, a strong founder effect has been described, with four recurrent ATM mutations accounting for most cases. Methods A retrospective observational study was conducted using the molecular registry of the National Children’s Hospital in Costa Rica. Patients with a clinical diagnosis of A-T and molecular confirmation of biallelic ATM mutations were included. Genetic data were analyzed to determine allele frequencies, homozygosity, and associations with consanguinity. Cancer occurrence in patients and family history of malignancy were systematically recorded. Results Forty-two patients with confirmed A-T were analyzed, corresponding to 84 ATM alleles. Founder mutations predominated, with CRAT-A being the most frequent allele (51.2%), followed by CRAT-D (23.8%) and CRAT-C (11.9%); CRAT-B was rare (1.2%). Over 60% of patients carried at least one CRAT-A allele, and approximately one third were homozygous for a founder mutation. Parental consanguinity, documented in 11.9% of cases, was significantly associated with homozygosity (odds ratio [OR] 8.39; p = 0.013), supporting a shared ancestral origin of these variants. Cancer was diagnosed in 14% of patients, and all malignancies were B cell lymphomas. No statistically significant association was identified between specific founder mutations and cancer development. However, a family history of cancer was present in 33% of patients, most commonly breast and gastric cancer. Mothers and maternal aunts were the most frequently affected relatives, consistent with the increased cancer risk reported in heterozygous ATM carriers. Conclusions This study confirms a strong ATM founder effect in Costa Rica, with CRAT-A as the predominant allele, and demonstrates a significant association between consanguinity and homozygosity. Although cancer occurrence in patients with A-T was not linked to specific founder mutations, the high frequency of lymphoid malignancies and the substantial burden of familial cancer highlight the need for structured oncologic surveillance and targeted genetic counseling for affected families. These findings support population-specific diagnostic strategies and long-term cancer risk assessment in both patients with A-T and heterozygous ATM carriers.