Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, China.
Institute of Neurosciences, The Fourth Military Medical University, Xi'an, Shaanxi, China.
Mol Genet Genomic Med. 2021 Jan;9(1):e1552. doi: 10.1002/mgg3.1552. Epub 2020 Dec 30.
Ambiguous or atypical phenotypes can make a definite diagnosis of primary immunodeficiency diseases based on biochemical indices alone challenging. Further, mortality in early life because of infections in patients with these conditions supports the use of genetic tests to facilitate rapid and accurate diagnoses.
Genetic and clinical analyses of three unrelated Chinese children with clinical manifestations of recurrent infections, who were considered to have primary immunodeficiency diseases, were conducted. Patient clinical features and serum immunological indices were recorded. Next-generation sequencing was used to screen for suspected pathogenic variants. Family co-segregation and in silico analysis were conducted to evaluate the pathogenicity of identified variants, following the American College of Medical Genetics and Genomics guidance.
All three patients were found to have predominant antibody defects. Sequencing analysis revealed that one had two compound heterozygous variants, c.255C>A and c.295C>T, in the autosomal gene, activation-induced cytidine deaminase (AICDA). The other two patients were each hemizygous for the variants c.1185G>A and c.82C>T in the Bruton's tyrosine kinase (BTK) gene on the X chromosome. In silico analysis revealed that identified substituted amino acids were highly conserved and predicted to cause structural and functional damage to the proteins.
Four pathogenic variants in AICDA and BTK were confirmed to cause different forms of hyper-IgM syndrome type 2 (HIGM2) and X-linked agammaglobulinemia (XLA); two were novel mutations that have never been reported previously. This is the first report of HIGM2 caused by AICDA deficiency in a patient from the Chinese mainland.
仅基于生化指标，具有模糊或非典型表型的原发性免疫缺陷疾病的明确诊断具有挑战性。此外，由于这些情况下的患者感染，早期死亡率支持使用基因检测来促进快速和准确的诊断。
对 3 名具有复发性感染临床表现且被认为患有原发性免疫缺陷疾病的中国汉族儿童进行了遗传和临床分析。记录了患者的临床特征和血清免疫学指标。使用下一代测序筛选疑似致病变异。根据美国医学遗传学与基因组学学院的指导，对鉴定的变异进行了家系共分离和计算机分析，以评估其致病性。
所有 3 名患者均发现主要存在抗体缺陷。测序分析显示，1 名患者在常染色体基因活化诱导胞苷脱氨酶（AICDA）中存在两个复合杂合变异，c.255C>A 和 c.295C>T。另外 2 名患者各携带 X 染色体上 Bruton 酪氨酸激酶（BTK）基因的 c.1185G>A 和 c.82C>T 变异的半合子。计算机分析表明，鉴定的取代氨基酸高度保守，并预测对蛋白质造成结构和功能损伤。
在 AICDA 和 BTK 中鉴定出的 4 个致病变异导致不同形式的高 IgM 综合征 2 型（HIGM2）和 X 连锁无丙种球蛋白血症（XLA）；其中 2 个是以前从未报道过的新突变。这是中国大陆首例由 AICDA 缺陷引起的 HIGM2 病例。
