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

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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.

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Acknowledgments

This research was supported by grant G.A044.10 from the Fund for Scientific Research Flanders (FWO) to KC, “Emmanuel van der Schueren” grant from the “Vlaamse Liga tegen Kanker” to PS and by the “VLIR Own Initiative Programme” ZEIN2011PR387 between Belgium and South Africa. Bruce Poppe is a senior clinical investigator for the Fund for Scientific Research Flanders (FWO). We would like to thank Mijke Verhagen for her helpful advices. AMRT thanks Cancer Research UK for continued support.

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Authors and Affiliations

  1. Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium

    Kathleen Claes, Annelot Baert, Peter Schietecatte, Bruce Poppe & Kim De Leeneer

  2. Department of Basic Medical Sciences, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium

    Julie Depuydt, Annelot Baert & Anne Vral

  3. School of Cancer Sciences, University of Birmingham, Birmingham, B15 2TT, UK

    A. Malcolm R. Taylor & James I. Last

  4. NRF iThemba LABS, PO Box 722, Somerset West, 7129, South Africa

    Veerle Vandersickel

  5. Department of Neurology and Child Neurology, AZ St-Jan, 8000, Brugge, Belgium

    Marc D’Hooghe

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  1. Kathleen Claes
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  2. Julie Depuydt
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  3. A. Malcolm R. Taylor
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Correspondence to Kathleen Claes.

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K. Claes, J. Depuydt, M. D’Hooghe and A. Vral contributed equally to this work.

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Claes, K., Depuydt, J., Taylor, A.M.R. et al. Variant Ataxia Telangiectasia: Clinical and Molecular Findings and Evaluation of Radiosensitive Phenotypes in a Patient and Relatives. Neuromol Med 15, 447–457 (2013). https://doi.org/10.1007/s12017-013-8231-4

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