European journal of immunology · 2025
Identification and Functional Validation of Novel Pathogenic Variants in Primary Immunodeficiencies.
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Vr Arvinden, Govindaraj Geeta Madathil, Iyer Aditya Ramdas, Paul Sangita, Edavazhippurath Athulya, Jain Abhinav, Gupta Pragya, Deshmukh Gauspasha Yusuf, Singh Shivani, Saravanakumar Vinodh, Bhardwaj Juhi, Sharma Srishti, Benny Tancia P, Saravanan Priya, Bhoyar Rahul C, Imran Mohamed, Senthivel Vigneshwar, Divakar Mohit Kumar, Vignesh Harie, Jolly Bani, Dalvi Aparna, Bargir Umair Ahmed, Madkaikar Manisha, Bk Binukumar, Sivasubbu Sridhar, Ramalingam Sivaprakash, Scaria Vinod
Аннотация
Primary immunodeficiency diseases (PIDs) are inherited disorders caused by genetic defects affecting immune function, leading to recurrent infections, autoimmunity, and malignancies. Many PIDs remain genetically uncharacterized, largely due to rare variants with unclear pathogenicity, which complicates the process of establishing an accurate diagnosis. Next-generation sequencing (NGS) technology enables the identification of molecular defects, improving the diagnosis of PIDs. Functional validation of genetic variants identified through PID-related gene screenings is crucial for determining their clinical significance. In this study, we identified five novel variants in PID-related genes in six families using whole-exome sequencing. These variants include FCHO1 (E44K), NCF2 (A206P), NCF2 (c.174 + 1G > A), STAT1 (L199F), and a copy number deletion in LRBA (exon 9-17). Functional validation was performed for four of these variants: STAT1 (L199F) using pSTAT1 assay, NCF2 (A206P and c.174 + 1G > A) by DHR assay, and FCHO1 (E44K) using CRISPR-mediated genome editing. Overall, the present study expands the knowledge of previously unreported variants in primary immunodeficiency.