Rapid molecular diagnostics of Severe Primary Immunodeficiency by targeted next generation sequencing

Published Online: July 11. 2016

Severe combined immunodeficiency (SCID), also known as the bubble boy disease, is the most serious form of primary immunodeficiency. Absence of functional T cells and in some cases B and NK cells at birth makes affected infants extremely vulnerable to infections. Therefore, SCID is fatal if not treated promptly and is considered a medical emergency since the outcome of bone marrow transplant is best when it is done before the first infection. Adding SCID to newborn screening has greatly improved SCID detection.  However, false positives do occur in newborn screening and there is a need for a confirmatory test that can be done in the clinical laboratory as opposed to the research setting.  

In a research article just published in The Journal of Allergy & Clinical Immunology (JACI), Yu and colleagues utilized high-throughput next generation sequencing (NGS) technologies to examine 46 genes known to cause severe immunodeficiencies in one test, providing an effective genotype-based approach to definitive molecular diagnosis of SCID and related disorders for rapid clinical diagnosis and potential gene directed therapeutic actions.

The authors developed and validated the NGS-based multi-gene panel in a clinical laboratory setting. They analyzed 20 patient samples with abnormal newborn screening results or positive family history and identified deleterious mutations in 14 of them. The NGS analysis of deeply covered targeted gene regions enabled detection of single nucleotide variants (SNV) and intragenic copy number variants (CNV), such as exonic deletion alleles, in 10 different genes.

Comprehensive NGS analysis allows early and accurate molecular diagnosis of genetically heterogeneous SCID and other severe primary immunodeficiency diseases, ensuring timely life-saving treatment and optimal clinical management. This study has future implications for the time when gene directed therapy becomes a reality.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

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