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

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.

SUBMITTER: Arunachalam AK

PROVIDER: S-EPMC7610931 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRecently, a growing number of novel genetic defects underlying primary immunodeficiencies (PIDs) have been identified, increasing the number of PID up to more than 250 well-defined forms. Next-generation sequencing (NGS) technologies and proper filtering strategies greatly contributed to this rapid evolution, providing the possibility to rapidly and simultaneously analyze large numbers of genes or the whole exome.ObjectiveTo evaluate the role of targeted NGS and whole exome sequencing (WES) in the diagnosis of a case series, characterized by complex or atypical clinical features suggesting a PID, difficult to diagnose using the current diagnostic procedures.MethodsWe retrospectively analyzed genetic variants identified through targeted NGS or WES in 45 patients with complex PID of unknown etiology.ResultsForty-seven variants were identified using targeted NGS, while 5 were identified using WES. Newly identified genetic variants were classified into four groups: (I) variations associated with a well-defined PID, (II) variations associated with atypical features of a well-defined PID, (III) functionally relevant variations potentially involved in the immunological features, and (IV) non-diagnostic genotype, in whom the link with phenotype is missing. We reached a conclusive genetic diagnosis in 7/45 patients (~16%). Among them, four patients presented with a typical well-defined PID. In the remaining three cases, mutations were associated with unexpected clinical features, expanding the phenotypic spectrum of typical PIDs. In addition, we identified 31 variants in 10 patients with complex phenotype, individually not causative per se of the disorder.ConclusionNGS technologies represent a cost-effective and rapid first-line genetic approach for the evaluation of complex PIDs. WES, despite a moderate higher cost compared to targeted, is emerging as a valuable tool to reach in a timely manner, a PID diagnosis with a considerable potential to draw genotype-phenotype correlation. Nevertheless, a large fraction of patients still remains without a conclusive diagnosis. In these patients, the sum of non-diagnostic variants might be proven informative in future studies with larger cohorts of patients.

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

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