Data_Sheet_1_Complex Inheritance of Rare Missense Variants in PAK2, TAP2, and PLCL1 Genes in a Consanguineous Arab Family With Multiple Autoimmune Diseases Including Celiac Disease.docx

BackgroundAutoimmune diseases (AIDs) share a common molecular etiology and often present overlapping clinical presentations. Thus, this study aims to explore the complex molecular basis of AID by whole exome sequencing and computational biology analysis.
MethodsMolecular screening of the consanguineous AID family and the computational biology characterization of the potential variants were performed. The potential variants were searched against the exome data of 100 healthy individuals and 30 celiac disease patients.
ResultA complex inheritance pattern of PAK2 (V43A), TAP2 (F468Y), and PLCL1 (V473I) genetic variants was observed in the three probands of the AID family. The PAK2 variant (V43A) is a novel one, but TAP2 (F468Y) and PLCL1 (V473I) variants are extremely rare in local Arab (SGHP and GME) and global (gnomAD) databases. All these variants were localized in functional domains, except for the PAK2 variant (V43A) and were predicted to alter the structural (secondary structure elements, folding, active site confirmation, stability, and solvent accessibility) and functional (gene expression) features. Therefore, it is reasonable to postulate that the dysregulation of PAK2, TAP2, and PLCL1 genes is likely to elicit autoimmune reactions by altering antigen processing and presentation, T cell receptor signaling, and immunodeficiency pathways.
ConclusionOur findings highlight the importance of exploring the alternate inheritance patterns in families presenting complex autoimmune diseases, where classical genetic models often fail to explain their molecular basis. These findings may have potential implications for developing personalized therapies for complex disease patients.

背景 自身免疫性疾病（Autoimmune diseases, AIDs）具有共同的分子发病机制，且临床表型常存在重叠。因此，本研究旨在通过全外显子测序（whole exome sequencing）与计算生物学分析，探究自身免疫性疾病复杂的分子基础。
方法 本研究对近亲婚配的自身免疫性疾病家系开展分子筛查，并对潜在变异进行计算生物学表征。通过检索100名健康个体与30名乳糜泻患者的外显子组数据，完成对上述潜在变异的筛选验证。
结果 在该自身免疫性疾病家系的3名先证者中，观察到PAK2（V43A）、TAP2（F468Y）与PLCL1（V473I）遗传变异的复杂遗传模式。其中PAK2变异（V43A）为新发变异，而TAP2（F468Y）与PLCL1（V473I）变异在本地阿拉伯人群数据库（SGHP与GME）及全球人群数据库（gnomAD）中极为罕见。除PAK2变异（V43A）外，所有变异均定位于功能结构域，且被预测可改变蛋白质的结构特征（二级结构元件、折叠方式、活性位点构象、稳定性与溶剂可及性）及功能特征（基因表达水平）。据此可推测，PAK2、TAP2与PLCL1基因的表达失调，可能通过改变抗原加工与呈递、T细胞受体信号通路以及免疫缺陷相关通路，诱发自身免疫反应。
结论 本研究结果凸显了在经典遗传模型难以阐明其分子基础的复杂自身免疫性疾病家系中，探究非典型遗传模式的重要性。上述发现或可为复杂疾病患者的个性化治疗研发提供潜在参考价值。