Primary Immunodeficiencies in India: Molecular Diagnosis and the Role of Next-Generation Sequencing
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ORIGINAL ARTICLE
Primary Immunodeficiencies in India: Molecular Diagnosis and the Role of Next-Generation Sequencing Arun Kumar Arunachalam 1 & Madhavi Maddali 1 & Fouzia N. Aboobacker 1 & Anu Korula 1 & Biju George 1 & Vikram Mathews 1 & Eunice Sindhuvi Edison 1 Received: 1 July 2020 / Accepted: 13 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Primary immunodeficiency . targeted gene panel . clinical exome sequencing . mutations . next-generation sequencing . India
Introduction Primary immunodeficiency diseases (PIDs) are a heterogeneous group of monogenic inherited disorders with varying degrees of immunodeficiency and immune dysregulation thereby predisposing the patients to infections, autoimmune diseases, and malignancies [1–3]. With the introduction and subsequent dominance of next-generation sequencing (NGS) in the last two decades, there has been substantial growth in the number of PIDs and our knowledge of the underlying genetic defects [4, 5]. The 2017 IUIS (International Union of Immunological Societies) classification had 354 PIDs with 344 underlying genetic defects which increased to 404
* Eunice Sindhuvi Edison [email protected] 1
Department of Hematology, Christian Medical College, Vellore, Tamil Nadu 632004, India
diseases with 430 underlying genetic defects in the 2019 update [1, 6]. Studies have shown strong ethnic and geographic predispositions to various P
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