Analysis of Clinical and Genetic Characterization of Three Ataxia–Telangiectasia Pedigrees With Novel ATM Gene Mutations

Frontiers in Pediatrics

article

Peng Huang¹  Lu Zhang¹  Li Tang¹  Yi Ren¹  Hong Peng¹  Jie Xiong¹  Lingjuan Liu¹  Jie Xu¹  Yangyang Xiao¹  Jian Li¹  Dingan Mao¹  Liqun Liu¹ 

[1] Department of Pediatrics, The Second Xiangya Hospital of Central South University;Children's Brain Development and Brain Injury Research Office, The Second Xiangya Hospital of Central South University

关键词: ataxia–telangiectasia;    AT;    ATM gene;    Whole-exome sequencing;    Sanger sequencing;   

DOI  :  10.3389/fped.2022.877826

学科分类：社会科学、人文和艺术（综合）

来源: Frontiers

【 摘 要 】

Objective The clinical manifestations of ataxia–telangiectasia (AT) are very complex and are easily misdiagnosed and missed. The purpose of this study was to explore the clinical characteristics and genetic features of five pediatric patients with AT from three pedigrees in china. Methods Retrospectively collected and analyzed the clinical data and genetic testing results of five AT patients diagnosed by the Whole-exome sequencing followed by Sanger sequencing. The five patients with AT were from three pedigrees, including two female patients (case 1 and case 2) in pedigree I, one male patient (case 3) in pedigree II, and two male patients (case 4 and case 5) in pedigree III. According to the United Kingdom Association for Clinical Genomic Science Best Practice Guidelines for Variants Classification in Rare Disease 2020 to grade the genetic variants. Results Five patients had mainly clinical presentations including unsteady gait, dysarthria, bulbar conjunctive telangiectasia, cerebellar atrophy, intellectual disability, stunted growth, increase of alpha-fetoprotein in serum, lymphopenia. Notably, one patient with classical AT presented dystonia as the first symptom. One patient had recurrent infections, five patients had serum Immunoglobulin (Ig) A deficiency, and two patients had IgG deficiency. In three pedigrees, we observed five pathogenic variants of the ATM gene, which were c.1339C>T (p.Arg447Ter), c.7141_7151delAATGGAAAAAT (p.Asn2381GlufsTer18), c.437_440delTCAA (p.Leu146GlnfsTer6), c.2482A>T (p.Lys828Ter), and c.5495_5496+2delAAGT (p.Glu1832GlyfsTer4). Moreover, the c.437_440delTCAA, c.2482A>T, and c.5495_5496+2delAAGT were previously unreported variants. Conclusions Pediatric patients with classical AT may present dystonia as the main manifestation, or even a first symptom, besides typical cerebellar ataxia, bulbar conjunctive telangiectasia, etc. Crucially, we also found three novel pathogenic ATM gene variants (c.437_440delTCAA, c.2482A>T, and c.5495_5496+2delAAGT), expanding the ATM pathogenic gene mutation spectrum.

【 授权许可】

CC BY