AUTHOR=Alharthi Arwa Mastoor , Banaganapalli Babajan , Hassan Sabah M. , Rashidi Omran , Al-Shehri Bandar Ali , Alaifan Meshari A. , Alhussaini Bakr H. , Alsufyani Hadeel A. , Alghamdi Kawthar Saad , Nasser Khalda Khalid , Bin-Taleb Yagoub , Elango Ramu , Shaik Noor Ahmad , Saadah Omar I. 

TITLE=Complex Inheritance of Rare Missense Variants in PAK2, TAP2, and PLCL1 Genes in a Consanguineous Arab Family With Multiple Autoimmune Diseases Including Celiac Disease

JOURNAL=Frontiers in Pediatrics

VOLUME=10

YEAR=2022

URL=https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2022.895298

DOI=10.3389/fped.2022.895298

ISSN=2296-2360

ABSTRACT=<sec><title>Background</title><p>Autoimmune 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.</p></sec><sec><title>Methods</title><p>Molecular 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.</p></sec><sec><title>Result</title><p>A complex inheritance pattern of <italic>PAK2</italic> (V43A), <italic>TAP2</italic> (F468Y), and <italic>PLCL1</italic> (V473I) genetic variants was observed in the three probands of the AID family. The <italic>PAK2</italic> variant (V43A) is a novel one, but <italic>TAP2</italic> (F468Y) and <italic>PLCL1</italic> (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 <italic>PAK2</italic> 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 <italic>PAK2</italic>, <italic>TAP2</italic>, and <italic>PLCL1 genes</italic> is likely to elicit autoimmune reactions by altering antigen processing and presentation, T cell receptor signaling, and immunodeficiency pathways.</p></sec><sec><title>Conclusion</title><p>Our 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.</p></sec>