Variant Ataxia Telangiectasia: Clinical and Molecular Findings and Evaluation of Radiosensitive Phenotypes in a Patient and Relatives

Abstract

Variant ataxia telangiectasia (A-T) may be an underdiagnosed entity. We correlate data from radiosensitivity and kinase assays with clinical and molecular data from a patient with variant A-T and relatives. The coding region of ATM was sequenced. To evaluate the functional effect of the mutations, we performed kinase assays and developed a novel S-G2 micronucleus test. Our patient presented with mild dystonia, moderately dysarthric speech, increased serum α-fetoprotein but no ataxia nor telangiectasias, no nystagmus or oculomotor dyspraxia. She has a severe IgA deficiency, but does not have recurrent infections. She is compound heterozygote for ATM c.8122G>A (p.Asp2708Asn) and c.8851-1G>T, leading to in frame loss of 63 nucleotides at the cDNA level. A trace amount of ATM protein is translated from both alleles. Residual kinase activity is derived only from the p.Asp2708Asn allele. The conventional G0 micronucleus test, based on irradiation of resting lymphocytes, revealed a radiosensitive phenotype for the patient, but not for the heterozygous relatives. As ATM is involved in homologous recombination and G2/M cell cycle checkpoint, we optimized an S-G2 micronucleus assay, allowing to evaluate micronuclei in lymphocytes irradiated in the S and G2 phases. This test showed increased radiosensitivity for both the patient and the heterozygous carriers. Intriguingly, heterozygous carriers of c.8851-1G>T (mutation associated with absence of kinase activity) showed a stronger radiosensitive phenotype with this assay than heterozygous carriers of p.Asp2708Asn (mutation associated with residual kinase activity). The modified S-G2 micronucleus assay provided phenotypic insight into complement the diagnosis of this atypical A-T patient.

A low‐frequency haplotype spanning SLX4/FANCP constitutes a new risk locus for early‐onset breast cancer (<60 years) and is associated with reduced DNA repair capacity

“…Furthermore, the dependence on age and genotype demonstrates the inherent causal relationship between all three associations. In addition to the detection of heterozygotes of ATM and BRCA1 mutations by the MNT, our data provide one of the few examples of a strong correlation between a genotype and induced MN frequency and thus support the relevance of induced MN frequencies in the context of breast cancer research. The additional use of induced MN frequency on cases carrying the risk haplotype allows to identify those who carry the suspected “causal variant” with high accuracy (AUC >0.9) among the BC cases with an age of onset ≤60 years and may thus help to identify the causal variant.…”

“…Many of the susceptibility genes for breast cancer are involved in the removal of DNA interstrand cross‐links and repair of double strand breaks and several are constituents of the Fanconi anemia DNA repair pathway. Heterozygous deleterious mutations in these genes have been assumed to manifest in a reduced DNA repair capacity, which has been demonstrated repeatedly (for example and in two instances ( BRCA1 and ATM ) with the MN test. The association between MN frequencies with or without mutagenic challenge and breast cancer in general has been frequently addressed in studies searching for biomarkers of breast cancer risk .…”

Analysis of chromosomal radiosensitivity of healthy BRCA2 mutation carriers and non-carriers in BRCA families with the G2 micronucleus assay

“…We previously used this assay and confirmed radiosensitivity in healthy BRCA1 mutation carriers (n=18) compared to healthy controls without a family history of BC or OC (n=20) (12), and in an ataxia-telangiectasia patient and family members (27). In addition, we also included healthy relatives not carrying the familial germline BRCA1 or BRCA2 mutation in the present study.…”

Ataxia‐telangiectasia: recommendations for multidisciplinary treatment

“…3,4 In the clinical context mentioned above, an elevated serum a-fetoprotein level 5 and immune deficiencies suggest the diagnosis of ataxia-telangiectasia. Important complications arise from a compromised immune system, progressive respiratory failure, and an increased risk of malignancies.…”

“…Recently, gabapentin was shown to have positive effects on severe dystonia in children. 13 4-Aminopyridine has been shown to improve oculomotor and vestibular function in a non-randomized trial including four patients with ataxia-telangiectasia. Deep brain stimulation may be considered if the therapies mentioned above are not beneficial.…”