Date Published: October 6, 2015
Publisher: Public Library of Science
Author(s): Zhao Chen, Wei Ye, Zhe Long, Dongxue Ding, Huirong Peng, Xuan Hou, Rong Qiu, Kun Xia, Beisha Tang, Hong Jiang, Robert S. Weiss.
Ataxia telangiectasia (AT) is an autosomal recessive disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia and immunodeficiency due to mutations in the ATM gene. We performed targeted next-generation sequencing (NGS) on three unrelated patients and identified five disease-causing variants in three probands, including two pairs of heterozygous variants (FAT–1:c.4396C>T/p.R1466X, c.1608-2A>G; FAT–2:c.4412_4413insT/p.L1472Ffs*19, c.8824C>T/p.Q2942X) and one pair of homozygous variants (FAT–3: c.8110T>G/p.C2704G, Hom). With regard to precision medicine for rare genetic diseases, targeted NGS currently enables the rapid and cost-effective identification of causative mutations and is an updated molecular diagnostic tool that merits further optimization. This high-throughput data-based strategy would propel the development of precision diagnostic methods and establish a foundation for precision medicine.
Ataxia telangiectasia (AT, MIM#208900), due to mutations in the ataxia telangiectasia mutated gene (ATM, MIM*600118), is an autosomal recessive disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia and immunodeficiency, as well as elevated α-fetoprotein (AFP) serum levels, immunoglobulin deficiency and predisposition to cancers[1–4]. Typically occurring early in childhood, AT patients usually die in their twenties due to malignancies or respiratory failure. Since two Chinese AT patients were first described in our previous work, very few AT cases have been reported in China [5–7]. For such a rare genetic disease, the advent of precision medicine that aims to generate individualized approaches for prevention, diagnosis and treatment would provide broad insight into genetic diagnosis and counselling . Targeted next-generation sequencing (NGS) currently allows the rapid and cost-effective identification of causative mutations and is an updated molecular diagnostic tool that merits further optimization. In this study, we performed targeted NGS on three unrelated AT patients whose diagnoses were confirmed by the identification of disease-causing variants, thereby illustrating the utility of NGS in precision medicine.
AT is a multisystem autosomal recessive disorder caused by mutation of ATM gene. To date, more than 780 mutations have been reported (http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ATM), include missense, nonsense, splicing, small indels, large deletions, and duplications in the 66 exons of the ATM gene without apparent hotspots. Most of missense mutations responsible for AT often lead to ATM protein underexpression . In this study, we made the accurate genetic diagnoses on three AT patients due to typical clinical symptoms combined with identification of five causative variants of ATM gene via targeted next-generation sequencing. The finding of novel mutations would broaden the genotypic spectrum of the ATM gene, which is beneficial for better understanding the relationship between the genotype and phenotype of AT.