Dataset Information

Clinical and Genetic Spectrum of Inborn Errors of Immunity in a Tertiary Care Center in Southern India.

ABSTRACT:

Objectives

To study the incidence, clinical manifestations, and genetic spectrum of primary immunodeficiency diseases (PID)/inborn errors of immunity (IEI) in a tertiary care hospital in Southern India.

Methods

A retrospective analysis of all patients with a clinical suspicion of PID/IEI seen at a tertiary care hospital was performed. All patients had at least one or more warning signs of PID. Serum immunoglobulin levels and other targeted investigations were performed as warranted by the clinical presentation. All families with suspected PID were counseled and offered genetic testing.

Results

A total of 225 children were evaluated for PID during the study period of 6 y. Fifty-six of them did not meet the European Society of Immunodeficiencies (ESID) criteria (working definition of clinical diagnosis) and were excluded. An IEI was found in 30/49 (61.2%) patients. The most frequent reason for referral was recurrent/unusual or serious infections (28%), or cytopenia (16%). Group IV diseases of immune dysregulation was the most common category (19%), followed by group III predominant antibody deficiencies in 23/163 (14%), as per the International Union of Immunological Societies (IUIS) classification.

Conclusions

This study highlights the heterogeneity of the present cohort, the underuse of genetic tests, and efforts to provide optimal care for children with possible IEI in this center.

SUBMITTER: Lashkari HP

PROVIDER: S-EPMC8857151 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Clinical and Genetic Spectrum of Inborn Errors of Immunity in a Tertiary Care Center in Southern India.

Lashkari Harsha Prasada HP Madkaikar Manisha M Dalvi Aparna A Gupta Maya M Bustamante Jacinta J Sharma Madhubala M Rawat Amit A Bhatia Prateek P Bhat Kamalakshi G KG Rao Sadashiva S Kamath Nutan N Moideen Faheem F Latour Sylvain S Winter Sarah S Bhavani Gandham SriLakshmi GS Girisha Katta M KM

Indian journal of pediatrics 20211126 3

<h4>Objectives</h4>To study the incidence, clinical manifestations, and genetic spectrum of primary immunodeficiency diseases (PID)/inborn errors of immunity (IEI) in a tertiary care hospital in Southern India.<h4>Methods</h4>A retrospective analysis of all patients with a clinical suspicion of PID/IEI seen at a tertiary care hospital was performed. All patients had at least one or more warning signs of PID. Serum immunoglobulin levels and other targeted investigations were performed as warrante ...[more]

PMID: 34826056

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Project description:Background: Inborn errors of metabolism are rare genetic disorders; however, these are prevalent in countries with high consanguinity rates, like Lebanon. Patients are suspected, based on a combination of clinical and biochemical features; however, the final confirmation relies on genetic testing. Using next generation sequencing, as a new genetic investigational tool, carries several challenges for the physician, the geneticist, and the families. Methods: In this retrospective study, we analyzed the clinical, biochemical, and genetic profile of inborn errors of metabolism suspected patients, seen at a major tertiary care center in Lebanon, between 2015 and 2018. Genetic testing was performed using next generation sequencing. Genotype-phenotype correlation and diagnostic yield of each testing modality were studied. Results: Out of 211 patients genetically tested, 126 were suspected to have an inborn error of metabolism. The diagnostic yield of next generation sequencing reached 64.3%. Single gene testing was requested in 53%, whole exome sequencing in 36% and gene panels in 10%. Aminoacid disorders were mostly diagnosed followed by storage disorders, organic acidemias and mitochondrial diseases. Targeted testing was performed in 77% of aminoacid and organic acid disorders and half of suspected storage disorders. Single gene sequencing was positive in 75%, whereas whole exome sequencing diagnostic yield for complex cases, like mitochondrial disorders, reached 49%. Good clinical and biochemical correlation allowed the interpretation of variants of unknown significance and negative mutations as well as therapeutic management of most patients. Conclusion: Tailoring the choice of test modality, by next generation sequencing, to the category of suspected inborn errors of metabolism may lead to rapid diagnosis, shortcutting the cost of repeated testing. Whole exome sequencing as a first-tier investigation may be considered mainly for suspected mitochondrial diseases, whereas targeted sequencing can be offered upon suspicion of a specific enzyme deficiency. Timing and modality of gene test remain challenging, in view of the cost incurred by families.

Project description:BackgroundInherited genetic defects in immune system-related genes can result in Inborn Errors of Immunity (IEI), also known as Primary Immunodeficiencies (PID). Diagnosis of IEI disorders is challenging due to overlapping clinical manifestations. Accurate identification of disease-causing germline variants is crucial for appropriate treatment, prognosis, and genetic counseling. However, genetic sequencing is challenging in low-income countries like Brazil. This study aimed to perform genetic screening on patients treated within Brazil's public Unified Health System to identify candidate genetic variants associated with the patient's phenotype.MethodsThirteen singleton unrelated patients from three hospitals in Rio de Janeiro were enrolled in this study. Genomic DNA was extracted from the peripheral blood lymphocytes of each patient, and whole exome sequencing (WES) analyses were conducted using Illumina NextSeq. Germline genetic variants in IEI-related genes were prioritized using a computational framework considering their molecular consequence in coding regions; minor allele frequency ≤ 0.01; pathogenicity classification based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines gathered from the VarSome clinical database; and IEI-related phenotype using the Franklin tool. The genes classification into IEI categories follows internationally recognized guidelines informed by the International Union of Immunological Societies Expert Committee. Additional methods for confirmation of the variant included Sanger sequencing, phasing analysis, and splice site prediction.ResultsA total of 16 disease-causing variants in nine genes, encompassing six different IEI categories, were identified. X-Linked Agammaglobulinemia, caused by BTK variations, emerged as the most prevalent IEI disorder in the cohort. However, pathogenic and likely pathogenic variants were also reported in other known IEI-related genes, namely CD40LG, CARD11, WAS, CYBB, C6, and LRBA. Interestingly, two patients with suspected IEI exhibited pathogenic variants in non-IEI-related genes, ABCA12 and SLC25A13, potentially explaining their phenotypes.ConclusionsGenetic screening through WES enabled the detection of potentially harmful variants associated with IEI disorders. These findings contribute to a better understanding of patients' clinical manifestations by elucidating the genetic basis underlying their phenotypes.

Dataset Information

Clinical and Genetic Spectrum of Inborn Errors of Immunity in a Tertiary Care Center in Southern India.

Objectives

Methods

Results

Conclusions

Publications

Clinical and Genetic Spectrum of Inborn Errors of Immunity in a Tertiary Care Center in Southern India.

Similar Datasets

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