Claes K., Depuydt J., Taylor A.M.R., Last J.I., Baert A., Schietecatte P., Vandersickel V., Poppe B., De Leeneer K., D'Hooghe M., Vral A.
Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium; Department of Basic Medical Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; NRF IThemba LABS, PO Box 722, Somerset West 7129, South Africa; Department of Neurology and Child Neurology AZ St-Jan, 8000 Brugge, Belgium
Claes, K., Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium; Depuydt, J., Department of Basic Medical Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Taylor, A.M.R., School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; Last, J.I., School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; Baert, A., Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium, Department of Basic Medical Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Schietecatte, P., Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium; Vandersickel, V., NRF IThemba LABS, PO Box 722, Somerset West 7129, South Africa; Poppe, B., Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium; De Leeneer, K., Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium; D'Hooghe, M., Department of Neurology and Child Neurology AZ St-Jan, 8000 Brugge, Belgium; Vral, A., Department of Basic Medical Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
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. © 2013 Springer Science+Business Media New York.