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Primary Immunodeficiencies in India: Molecular Diagnosis and the Role of Next-Generation Sequencing

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Abstract

Primary immunodeficiency diseases (PIDs) are a group of clinically and genetically heterogeneous disorders showing ethnic and geographic diversities. Next-generation sequencing (NGS) is a comprehensive tool to diagnose PID. Although PID is common in India, data on the genetic spectrum of PIDs are limited due to financial restrictions. The study aims to characterize the clinical and genetic spectrum of PID patients in India and highlight the importance of a cost-effective targeted gene panel sequencing approach for PID in a resource-limited setting. The study includes 229 patients with clinical and laboratory features suggestive of PIDs. Mutation analysis was done by Sanger sequencing and NGS targeting a customized panel of genes. Pathogenic variants were identified in 97 patients involving 42 different genes with BTK and IL12RB1 being the most common mutated genes. Autosomal recessive and X-linked recessive inheritance were seen in 51.6% and 23.7% of patients. Mendelian susceptibility to mycobacterial diseases (MSMD) and IL12RB1 mutations was more common in our population compared to the Western world and the Middle East. Two patients with hypomorphic RAG1 mutations and one female with skewed CYBB mutation were also identified. Another 40 patients had variants classified as variants of uncertain significance (VUS). The study shows that targeted NGS is an effective diagnostic strategy for PIDs in countries with limited diagnostic resources. Molecular diagnosis of PID helps in genetic counseling and to make therapeutic decisions including the need for a stem cell transplantation.

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Data Availability

The data that support the study findings are available from the corresponding author upon reasonable request.

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Acknowledgments

We respectfully thank all the patients and their families for their participation in this study. We extend our gratitude to Dr. Michael Lenardo, NIH, for his support in initiating this study at our center and for his expert comments and critical review of the manuscript. We thank Mr. Neelakandan and other staffs of the molecular laboratory for the technical support and carrying out molecular analysis. Validation of our bioinformatics analysis and results was performed by Varminer—a variant identification and interpretation tool developed by Medgenome Labs, Bangalore, India.

Funding

This study was in part supported by the department educational funds. No specific grant was received from any funding agency—private, or otherwise.

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Authors and Affiliations

  1. Department of Hematology, Christian Medical College, Vellore, Tamil Nadu, 632004, India

    Arun Kumar Arunachalam, Madhavi Maddali, Fouzia N. Aboobacker, Anu Korula, Biju George, Vikram Mathews & Eunice Sindhuvi Edison

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  1. Arun Kumar Arunachalam
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  7. Eunice Sindhuvi Edison
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by AKA, MM, and ESE. Clinical data and correlation were performed by FNA, AK, VM, and BG. The first draft of the manuscript was written by AKA and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Eunice Sindhuvi Edison.

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Research Involving Human and Animal Rights

The study was approved by the institutional research board (IRB Min No:9501 dated 15.02.2017). All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research and ethics committee. The study and the laboratory tests have been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki).

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Arunachalam, A.K., Maddali, M., Aboobacker, F.N. et al. Primary Immunodeficiencies in India: Molecular Diagnosis and the Role of Next-Generation Sequencing. J Clin Immunol 41, 393–413 (2021). https://doi.org/10.1007/s10875-020-00923-2

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