Varzari Alexander, Deyneko Igor V, Bruun Gitte Hoffmann, Dembic Maja, Hofmann Winfried, Cebotari Victor M, Ginda Sergei S, Andresen Brage S, Illig Thomas
Laboratory of Human Genetics, Chiril Draganiuc Institute of Phthisiopneumology, Kishinev, Moldova.
Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
Front Genet. 2022 Oct 20;13:969895. doi: 10.3389/fgene.2022.969895. eCollection 2022.
Inborn errors of immunity are known to influence susceptibility to mycobacterial infections. The aim of this study was to characterize the genetic profile of nine patients with mycobacterial infections (eight with BCGitis and one with disseminated tuberculosis) from the Republic of Moldova using whole-exome sequencing. In total, 12 variants in eight genes known to be associated with Mendelian Susceptibility to Mycobacterial Disease (MSMD) were detected in six out of nine patients examined. In particular, a novel splice site mutation c.373-2A>C in gene was found and functionally confirmed in a patient with disseminated tuberculosis. Trio analysis was possible for seven out of nine patients, and resulted in 23 candidate variants in 15 novel genes. Four of these genes - , , and were further prioritized, considering their elevated expression in immune-related tissues. Compound heterozygosity was found in in a single patient, comprising a maternally inherited missense variant c.412G>A/p.(Ala138Thr) predicted to be deleterious and a paternally inherited intronic mutation c.1149+14T>C. Functional studies demonstrated that the intronic mutation affects splicing and the level of transcript. Finally, we analyzed pathogenicity of variant combinations in gene pairs and identified five patients with putative oligogenic inheritance. In summary, our study expands the spectrum of genetic variation contributing to susceptibility to mycobacterial infections in children and provides insight into the complex/oligogenic disease-causing mode.
已知遗传性免疫缺陷会影响对分枝杆菌感染的易感性。本研究的目的是通过全外显子组测序来描述来自摩尔多瓦共和国的9例分枝杆菌感染患者（8例患有卡介苗病，1例患有播散性结核病）的基因图谱。在9例接受检测的患者中，有6例共检测到8个已知与孟德尔分枝杆菌病易感性（MSMD）相关基因中的12个变异。特别是，在1例播散性结核病患者中发现了一个新的剪接位点突变c.373-2A>C，并在功能上得到了证实。9例患者中有7例可以进行三联体分析，结果在15个新基因中发现了23个候选变异。考虑到这4个基因在免疫相关组织中的高表达，对其中4个基因—— 、 、 和 进行了进一步的优先排序。在1例患者的 基因中发现了复合杂合性，包括一个母系遗传的错义变异c.412G>A/p.(Ala138Thr)，预测为有害变异，以及一个父系遗传的内含子突变c.1149+14T>C。功能研究表明，内含子突变影响剪接和转录水平。最后，我们分析了基因对中变异组合的致病性，确定了5例具有假定寡基因遗传的患者。总之，我们的研究扩展了导致儿童对分枝杆菌感染易感性的遗传变异谱，并为复杂/寡基因致病模式提供了见解。
