Clinical diagnosis and genetic counseling of atypical ataxia‑telangiectasia in a Chinese family

Cao,Jiangxia; Shen,Ruiqin; Zhang,Wenqian; Mao,Bing; Shi,Qirong; Zhou,Rui; Liu,Zijing; Zeng,Bing; Chen,Xiaoling; Zhang,Cai; Lu,Min; Han,Peng; Wu,Jing; Zhou,Aifen; Tan,Xuemei

doi:10.3892/mmr.2019.9992

Clinical diagnosis and genetic counseling of atypical ataxia‑telangiectasia in a Chinese family

Authors:
- Jiangxia Cao
- Ruiqin Shen
- Wenqian Zhang
- Bing Mao
- Qirong Shi
- Rui Zhou
- Zijing Liu
- Bing Zeng
- Xiaoling Chen
- Cai Zhang
- Min Lu
- Peng Han
- Jing Wu
- Aifen Zhou
- Xuemei Tan
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Affiliations: Center for Prenatal Diagnosis, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China, BGI Genomics, BGI‑Shenzhen, Shenzhen, Guangdong 518083, P.R. China, Department of Neurology, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
Published online on: February 27, 2019 https://doi.org/10.3892/mmr.2019.9992
Pages: 3441-3448
Copyright: © Cao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ataxia‑telangiectasia (A‑T) is an autosomal recessive chromosome breakage disorder caused by mutations in the ATM serine/threonine kinase (ATM) gene. Typically, it presents in early childhood with progressive cerebellar dysfunction, accompanied by immunodeficiency and oculocutaneous telangiectasia. In the present study, the clinical and genetic findings of a Chinese family affected with A‑T in two live siblings, the proband (II‑2) and his elder brother (II‑1), as well as a fetus (II‑3) were reported. General health, clinical neurological, electrophysiological (motor and sensory nerve conduction) and magnetic resonance imaging evaluations revealed that patients II‑1 and II‑2 had similar symptoms of ataxia, dysarthria, conjunctival hyperemia and elevated serum α‑fetoprotein, whereas patient II‑1 had earlier A‑T onset at 2 years old and more serious problems with movement and intelligence. Targeted sequencing followed by Sanger sequencing revealed that these two patients carried the compound heterozygotes of a novel nonsense mutation c.5170G>T (p.Glu1724Ter) and a known nonsense mutation c.748C>T (p.Arg250Ter) in the ATM gene. Each mutation was inherited from an asymptomatic parent, which therefore confirmed the diagnosis of A‑T. Given this, proband's mother performed prenatal diagnosis in her third pregnancy. Unfortunately, the fetus had the same causal mutations as its siblings and the pregnancy was terminated. The findings of the present study expanded the mutation spectrum of the ATM gene and may help in understanding the genetic basis of A‑T, in order to guide genetic counseling and prenatal diagnosis.

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1	Gilad S, Chessa L, Khosravi R, Russell P, Galanty Y, Piane M, Gatti RA, Jorgensen TJ, Shiloh Y and Bar-Shira A: Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet. 62:551–561. 1998. View Article : Google Scholar : PubMed/NCBI
2	Schoenaker MH, Suarez F, Szczepanski T, Mahlaoui N and Loeffen JL: Treatment of acute leukemia in children with ataxia telangiectasia (A-T). Eur J Med Genet. 59:641–646. 2016. View Article : Google Scholar : PubMed/NCBI
3	National Cancer Institute. Ataxia telangiectasia, . Fact sheet. https://www.cancer.gov/about-cancer/causes-prevention/genetics/ataxia-fact-sheetDecember 18–2018
4	Chun HH and Gatti RA: Ataxia-telangiectasia, an evolving phenotype. DNA Repair (Amst). 3:1187–1196. 2004. View Article : Google Scholar : PubMed/NCBI
5	Tavani F, Zimmerman RA, Berry GT, Sullivan K, Gatti R and Bingham P: Ataxia-telangiectasia: The pattern of cerebellar atrophy on MRI. Neuroradiology. 45:315–319. 2003. View Article : Google Scholar : PubMed/NCBI
6	Waldmann TA and McIntire KR: Serum-alpha-fetoprotein levels in patients with ataxia-telangiectasia. Lancet. 2:1112–1115. 1972. View Article : Google Scholar : PubMed/NCBI
7	Jason JM and Gelfand EW: Diagnostic considerations in ataxia-telangiectasia. Arch Dis Child. 54:682–686. 1979. View Article : Google Scholar : PubMed/NCBI
8	Gatti RA, Berkel I, Boder E, Braedt G, Charmley P, Concannon P, Ersoy F, Foroud T, Jaspers NG, Lange K, et al: Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature. 336:577–580. 1988. View Article : Google Scholar : PubMed/NCBI
9	Chun HH, Sun X, Nahas SA, Teraoka S, Lai CH, Concannon P and Gatti RA: Improved diagnostic testing for ataxia-telangiectasia by immunoblotting of nuclear lysates for ATM protein expression. Mol Genet Metab. 80:437–443. 2003. View Article : Google Scholar : PubMed/NCBI
10	Xu Y, Gao P, Lv X, Zhang L and Zhang J: The role of the ataxia telangiectasia mutated gene in lung cancer: Recent advances in research. Ther Adv Respir Dis. 11:375–380. 2017. View Article : Google Scholar : PubMed/NCBI
11	Goodarzi AA, Jonnalagadda JC, Douglas P, Young D, Ye R, Moorhead GB, Lees-Miller SP and Khanna KK: Autophosphorylation of ataxia-telangiectasia mutated is regulated by protein phosphatase 2A. EMBO J. 23:4451–4461. 2014. View Article : Google Scholar
12	Kozlov SV, Graham ME, Jakob B, Tobias F, Kijas AW, Tanuji M, Chen P, Robinson PJ, Taucher-Scholz G, Suzuki K, et al: Autophosphorylation and ATM activation: Additional sites add to the complexity. J Biol Chem. 286:9107–9119. 2011. View Article : Google Scholar : PubMed/NCBI
13	Barlow C, Dennery PA, Shigenaga MK, Smith MA, Morrow JD, Roberts LJ II, Wynshaw-Boris A and Levine RL: Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs. Proc Natl Acad Sci USA. 96:9915–9919. 1999. View Article : Google Scholar : PubMed/NCBI
14	Yan M, Qiang W, Liu N, Shen J, Lynn WS and Wong PK: The ataxia-telangiectasia gene product may modulate DNA turnover and control cell fate by regulating cellular redox in lymphocytes. FASEB J. 15:1132–1138. 2001. View Article : Google Scholar : PubMed/NCBI
15	Yan M, Zhu C, Liu N, Jiang Y, Scofield VL, Riggs PK, Qiang W, Lynn WS and Wong PK: ATM controls c-Myc and DNA synthesis during postnatal thymocyte development through regulation of redox state. Free Radic Biol Med. 41:640–648. 2006. View Article : Google Scholar : PubMed/NCBI
16	Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER III, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, et al: ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 316:1160–1166. 2007. View Article : Google Scholar : PubMed/NCBI
17	Medical Research Council, . Aids to examination of the peripheral nervous system. Memorandum No. 45. Medical Research Council; London: 1976
18	Cornblath D: Electrophysiology in Guillain-Barre syndrome. Ann Neurol. 27 (Suppl):S17–S20. 1990. View Article : Google Scholar : PubMed/NCBI
19	Zhou X, Liao Y, Xu M, Ji Z, Xu Y, Zhou L, Wei X, Hu P, Han P, Yang F, et al: A novel mutation R190H in the AT-hook 1 domain of MeCP2 identified in an atypical Rett syndrome. Oncotarget. 8:82156–82164. 2017.PubMed/NCBI
20	Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al: Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the american college of medical genetics and genomics and the association for molecular pathology. Genet Med. 17:405–424. 2015. View Article : Google Scholar : PubMed/NCBI
21	Wei X, Ju X, Yi X, Zhu Q, Qu N, Liu T, Chen Y, Jiang H, Yang G, Zhen R, et al: Identification of sequence variants in genetic disease-causing genes using targeted next-generation sequencing. PLoS One. 6:e295002013. View Article : Google Scholar
22	Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS and Sunyaev SR: A method and server for predicting damaging missense mutations. Nat Methods. 7:248–249. 2010. View Article : Google Scholar : PubMed/NCBI
23	Kumar P, Henikoff S and Ng PC: Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 4:1073–1081. 2009. View Article : Google Scholar : PubMed/NCBI
24	Moulton J: Functional characterization and targeted correction of ATM mutations identified in Japanese patients with ataxia-telangiectasia. Hum Mutat. 33:198–208. 2015.
25	Teraoka SN, Telatar M, Becker-Catania S, Liang T, Onengüt S, Tolun A, Chessa L, Sanal O, Bernatowska E, Gatti RA and Concannon P: Splicing defects in the ataxia-telangiectasia gene, ATM: Underlying mutations and consequences. Am J Hum Genet. 64:1617–1631. 1999. View Article : Google Scholar : PubMed/NCBI
26	Buzin CH, Gatti RA, Nguyen VQ, Wen CY, Mitui M, Sanal O, Chen JS, Nozari G, Mengos A, Li X, Fujimura F and Sommer SS: Comprehensive scanning of the ATM gene with DOVAM-S. Hum Mutat. 21:123–131. 2010. View Article : Google Scholar
27	Lavin MF and Shiloh Y: The genetic defect in ataxia-telangiectasia. Ann Rev Immunol. 15:177–202. 2003. View Article : Google Scholar
28	Taylor AM, Byrd PJ, McConville CM and Thacker S: Genetic and cellular features of ataxia telangiectasia. Int J Radiat Biol. 65:65–70. 1994. View Article : Google Scholar : PubMed/NCBI
29	Kraus M, Lev A, Simon AJ, Levran I, Nissenkorn A, Levi YB, Berkun Y, Efrati O, Amariglio N, Rechavi G and Somech R: Disturbed B and T cell homeostasis and neogenesis in patients with ataxia telangiectasia. J Clin Immunol. 34:561–572. 2014. View Article : Google Scholar : PubMed/NCBI
30	Wright J, Teraoka S, Onengut S, Tolun A, Gatti RA, Ochs HD and Concannon P: A high frequency of distinct ATM gene mutations in ataxia-telangiectasia. Am J Hum Genet. 59:839–846. 1996.PubMed/NCBI
31	Concannon P and Gatti RA: Diversity of ATM gene mutations detected in patients with ataxia-telangiectasia. Hum Mutat. 10:100–107. 1997. View Article : Google Scholar : PubMed/NCBI
32	Li A and Swift M: Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients. Am J Med Genet. 92:170–177. 2010. View Article : Google Scholar
33	Jacquemin V, Rieunier G, Jacob S, Bellanger D, d'Enghien CD, Laugé A, Stoppa-Lyonnet D and Stern MH: Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations. Eur J Hum Genet. 20:305–312. 2012. View Article : Google Scholar : PubMed/NCBI