Dipartimento di Scienze della Vita e Sanità Pubblica, Sezione di Medicina Genomica, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy.
Research Unit of Medical Genetics, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy.
Genes (Basel). 2023 Jun 21;14(7):1310. doi: 10.3390/genes14071310.
Periodic fever syndromes include autoinflammatory disorders (AID) that involve innate immunity. These disorders are characterized by recurrent fevers and aberrant multi-organ inflammation, without any involvement of T or B cells or the presence of autoantibodies. A complex genetic architecture has been recognized for many AID. However, this complexity has only been partially uncovered for familial Mediterranean fever and other conditions that have a classical monogenic origin and Mendelian transmission. Several gene panels are currently available for molecular diagnosis in patients suspected of having AID. However, even when an extensive number of genes (up to 50-100) are tested in a cohort of clinically selected patients, the diagnostic yield of AID ranges between 15% and 25%, depending on the clinical criteria used for patient selection. In the remaining 75-85% of cases, it is conceivable that the causative gene or genes responsible for a specific condition are still elusive. In these cases, the disease could be explained by variants, either recessive or dominant, that have a major effect on unknown genes, or by the cumulative impact of different variants in more than one gene, each with minor additive effects. In this study, we focused our attention on five familial cases of AID presenting with classical autosomal dominant transmission. To identify the probable monogenic cause, we performed exome sequencing. Through prioritization, filtering, and segregation analysis, we identified a few variants for each family. Subsequent bioinformatics evaluation and pathway analysis helped to narrow down the best candidate genes for each family to , , , , and . Future studies on larger cohorts of familial cases will help confirm the pathogenic role of these genes in the pathogenesis of these complex disorders.
周期性发热综合征包括涉及固有免疫的自身炎症性疾病（AID）。这些疾病的特征是反复发热和异常的多器官炎症，没有 T 或 B 细胞的参与，也没有自身抗体的存在。许多 AID 的复杂遗传结构已经得到认可。然而，对于家族性地中海热和其他具有经典单基因起源和孟德尔遗传的疾病，这种复杂性仅部分得到揭示。目前有几种基因面板可用于疑似患有 AID 的患者的分子诊断。然而，即使在临床选择的患者队列中测试了大量基因（多达 50-100 个），AID 的诊断率仍在 15%至 25%之间，具体取决于用于患者选择的临床标准。在剩下的 75-85%的病例中，可以想象，导致特定疾病的致病基因或基因仍然难以捉摸。在这些情况下，疾病可能是由隐性或显性的变体引起的，这些变体对未知基因有重大影响，或者是由一个以上基因中的不同变体的累积影响引起的，每个变体都有较小的附加效应。在这项研究中，我们将注意力集中在五个具有经典常染色体显性遗传的家族性 AID 病例上。为了确定可能的单基因病因，我们进行了外显子组测序。通过优先级排序、过滤和分离分析，我们为每个家庭确定了几个变体。随后的生物信息学评估和途径分析有助于将每个家庭的最佳候选基因缩小到 、 、 、 和 。对更大的家族性病例队列的未来研究将有助于确认这些基因在这些复杂疾病发病机制中的致病作用。
