Molecular and Functional Characterization of a Cohort of Spanish Patients with Ataxia-Telangiectasia

Abstract

Ataxia-telangiectasia is a multisystemic disease with severe neurological affectation, immunodeficiency and telangiectasia. The disorder is caused by alterations in the ATM gene, whose size and complexity make molecular diagnosis difficult. We designed a target-enrichment next-generation sequencing strategy to characterize 28 patients from several regions of Spain. This approach allowed us to identify gene variants affecting function in 54 out of the 56 alleles analyzed, although the two unresolved alleles belong to brothers. We found 28 ATM gene mutations, of which 10 have not been reported. A total of 171 gene variants not affecting function were also found, of which 22 are reported to predispose to disease. Interestingly, all Roma (Spanish Gypsies) patients are homozygous for the same mutation and share the H3 ATM haplotype, which is strong evidence of a founder effect in this population. In addition, we generated a panel of 27 primary T cell lines from A-T patients, which revealed significant expression of ATM in two patients and traces of the protein in nine more. None of them retained residual ATM activity, and almost all T cell lines show increased or intermediate radiosensitivity.

Germline Genetic Findings Which May Impact Therapeutic Decisions in Families with a Presumed Predisposition for Hereditary Breast and Ovarian Cancer

“…Her daughter, IV.2, who carries the mutation, may benefit from prevention measures [2,3]. This mutation was previously reported in an Ataxia-Telangiectasia family [17]. In addition, other cancer types in this family have been associated with ATM mutations such as thyroid [18], ovarian [16] and breast tumours [15].…”

The spectrum of ATM gene mutations in Iranian patients with ataxia‐telangiectasia

“…Identifying mutations using conventional methods in A-T patients is challenging due to the large size of the ATM gene without apparent hot spots. Next-generation sequencing 39 technology is an accurate and cost-effective diagnostic method for A-T. 40 Here, we investigated the molecular basis of disease in 43 unrelated A-T pa- previously been reported. Furthermore, our results demonstrated that there is a significant correlation between phenotype severity and mutation severity.…”

Cutaneous Manifestations of Primary Immunodeficiency Diseases in Tunisian Children

“…This PID is caused by alterations in the ATM gene leading to telangiectasia, immunodeficiency with progressive ataxia and oculomotor apraxia often accompanied by extrapyramidal movement disorders. 21 , 22 In most cases, telangiectasias first appear when the child reaches three to five years of age. Conjunctival telangiectasias are first noted in the interpalpebral bulbar conjunctiva away from the limbus.…”