An updated review on Mendelian susceptibility to mycobacterial diseases– a silver jubilee celebration of its first genetic diagnosis

ABSTRACT

Introduction: Mendelian susceptibility to mycobacterial diseases (MSMD), a group of at least 18 different genetic disorders, encompasses a specific class of inborn errors of immunity that result in predilection to infection with mycobacteria including the weakly virulent strains. Primarily, these consist of defects in the IFN-γ-IL-12/23 circuit that is crucial for immunity against intracellular microorganisms. Although the first genetic etiology of MSMD was discovered in 1996, molecular diagnosis of MSMD in resource-constrained settings may remain far-fetched. Recently, original studies have emerged from developing countries, including India, wherein the genetic diagnosis was confirmed within the country itself. A lag of about 25 years, hence, seems to exist.

Areas covered: Herein, we review the clinical, laboratory, and mutational profiles of the genetic defects responsible for causing MSMD. We intend to enhance the recognition of these disorders in settings endemic for tuberculosis and bridge the gap between the developed and developing countries in the field of MSMD research and therapeutics.

Expert opinion: Research in the field of MSMD in developing countries, including India, can uncover novel genetic etiologies, as the population exceeds 1.3 billion, a huge burden of tuberculosis exists, and BCG vaccination is given universally at birth.

KEYWORDS:

• BCG
• flow cytometry
• genetics
• India
• MSMD
• mycobacterium tuberculosis

Article highlights

• MSMD encompasses a group of genetic defects characterized by impaired immunity against intracellular microbes including mycobacteria and Salmonella sp.

• Currently, more than 250 mutations in 18 genes have been reported to result in an MSMD phenotype.

• Diagnosis of MSMD has immense clinical implications in developing and tropical regions around the globe where tuberculosis (TB) and infections from other intracellular organisms like salmonella are often endemic.

• Technical and logistic constraints frequently hamper the molecular diagnosis of MSMD in resource-constrained settings.

• Diagnosis of MSMD may be obscured in regions with a huge burden of TB and/or enteric fever as infections from these organisms (including atypical clinical presentations) may be considered a norm rather than the result of an inborn error of immunity.

• In settings endemic for TB and/or salmonella infections, clinical implications of invasive infections from non-tuberculous mycobacteria and non-typhoidal salmonella may be overshadowed further hampering the recognition of MSMD.

• Research in the field of MSMD in developing and under-developed countries has the potential to uncover novel genetic etiologies as these regions comprise about two-thirds of the world population, many having a huge burden of mycobacterial and salmonella infections, and Bacillus Calmette–Guérin vaccination is frequently administered at birth.

Acknowledgments

We sincerely thank the Indian Council of Medical Research (ICMR) and the Department of Health Research (DHR), Government of India, for having sanctioned funding for the works related to Mendelian susceptibility to mycobacterial diseases (MSMD).

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

Ms Jhumki Das received salary from Indian Council of Medical Research (ICMR), Government of India (2019-6104/GEN-BMS) for her senior research fellowship in the project entitled, ‘Identification of monogenic defects in IL-12/IFN-gamma pathway in children with serious mycobacterial infection’. Dr Pandiarajan Vignesh received funding from Department of Health Research, Government of India (No.12014/62/2020-HR) for his research work entitled, ‘Assessment of inborn errors of immunity in serious forms of mycobacterial infections’. The funders have no role in the preparation of this manuscript.