Immunodeficiency, whether primary or secondary, results in the disruption of normal immune response and function. Typical presentations of immune deficiency are increased susceptibility to infection, usually in a specific class depending on the immune pathway or cell affected. [1,2] The phenotype is broad, and autoimmunity, immune dysregulation and increased risk for malignancy may also be hallmarks of the immunodeficiency. [2,3] In the absence of secondary immunodeficiency, severe infections in otherwise healthy children can alert clinicians to single-gene inborn errors of immunity or primary immunodeficiency disorders (PIDDs). [1,4] In tuberculosis (TB)-hyperendemic settings such as South Africa (SA), the risk for infection with TB cumulates with exposure, which provides an interesting context for the study of PIDD, in particular Mendelian susceptibility to mycobacterial disease (MSMD). [5][6][7][8] MSMD is molecularly characterised by errors in the interleukin 12 (IL-12) and interferon gamma (IFN-γ) pathway. [9] IFN-γ is a key cytokine in both innate and adaptive responses against viruses and intracellular bacteria, namely mycobacteria. [9][10][11] There is a dynamic balance between the host and the organism that determines the course of TB infection. [4,[12][13][14][15] The risk of progression to active disease is highest in infants aged <12 months and lowest in children aged 5 -10 years, the 'wonder years' . [6] Severe disease implies that there is either poor host control of the infection, i.e. dissemination, or a complex disease manifestation, often with severe sequelae such as TB empyema or pericarditis. [15] Non-severe disease implies that the host has managed to control the pathogen, resulting in contained disease. [15] Impaired response to IFN-γ is caused by mutations in the IFNGR1, IFNGR2, STAT1, CYBB, IRF8 and NEMO genes. [9,10] Deficient production of IFN-γ is associated with mutations in IL12B, IL12RB1, IL12RB2, TYK2, SPPL2a and ISG15. [9,10] MSMD is a PIDD characterised by selective predisposition to infections, typically with BCG or poorly pathogenic mycobacteria (e.g. Mycobacterium avium complex, M. kansasii, M. ghodii). [10,12] Individuals with MSMD are also predisposed to infection with M. tuberculosis complex (MTBC), Salmonella species, Listeria, Candida species, Toxoplasma species, and This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.
Primary immunodeficiency disorders (PIDs) are inborn errors of immunity (IEI) that cause immune system impairment. To date, more than 400 single-gene IEI have been well defined. The advent of next generation sequencing (NGS) technologies has improved clinical diagnosis and allowed for discovery of novel genes and variants associated with IEI. Molecular diagnosis provides clear clinical benefits for patients by altering management, enabling access to certain treatments and facilitates genetic counselling. Here we report on an 8-year experience using two different NGS technologies, namely research-based WES and targeted gene panels, in patients with suspected IEI in the South African healthcare system. A total of 52 patients’ had WES only, 26 had a targeted gene panel only, and 2 had both panel and WES. Overall, a molecular diagnosis was achieved in 30% (24/80) of patients. Clinical management was significantly altered in 67% of patients following molecular results. All 24 families with a molecular diagnosis received more accurate genetic counselling and family cascade testing. Results highlight the clinical value of expanded genetic testing in IEI and its relevance to understanding the genetic and clinical spectrum of the IEI-related disorders in Africa. Detection rates under 40% illustrate the complexity and heterogeneity of these disorders, especially in an African population, thus highlighting the need for expanded genomic testing and research to further elucidate this.
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