Mendelian Susceptibility to Mycobacterial Disease Panel

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare immunodeficiency syndrome with susceptibility to mycobacteria, such as environmental mycobacteria or the vaccine against tuberculosis [bacillus Calmette-Guérin (BCG)]. Individuals are typically resistant to infection with most other bacteria, fungi, viruses and parasites; however those with severe forms of disease may also be susceptible to these other pathogens (Qu et al. 2011. PubMed ID: 21330176; Bustamante et al. 2014. PubMed ID: 25453225). Beyond their susceptibility to weakly virulent mycobacteria, individuals with MSMD are typically healthy with no overt anomalies in routine hematological and immunological tests.

MSMD is characterized by severe, recurrent infections that may be disseminated or localized. There is significant allelic heterogeneity in the genes associated with MSMD and this is the reason for several different subtypes of MSMD. The most severe forms of MSMD develop in childhood and are characterized by serious, disseminated infections with mycobacteria that can affect the soft tissue, bone marrow, lungs, skin, bones and lymph nodes (Bustamante et al. 2014. PubMed ID: 25453225). Infections with other agents are often reported in those with early onset MSMD. More rarely, symptoms will develop during adolescence and adulthood and will usually be less severe. In addition, some genetically predisposed individuals may remain asymptomatic.

MSMD is a rare condition; its prevalence is not well established (Bustamante et al. 2014. PubMed ID: 25453225). There are many advantages of genetic testing for MSMD including informing treatment decisions such as antibiotic therapy, interferon gamma therapy, or hematopoietic stem cell transplantation, preventative measures such as avoidance of the BCG vaccine, and reproductive planning.

This test includes genes identified through literature, OMIM, and HGMD searches that have a reported association with MSMD.

MSMD are heterogeneous disorders that may be inherited in an autosomal dominant (AD), autosomal recessive (AR), and X-linked (XL) manner, with some genes having more than one mode of inheritance. In addition, MSMD variants may arise de novo. Causative variants may include missense, nonsense, splicing, regulatory, or copy number alterations (Qu et al. 2011. PubMed ID: 21330176).

The products of the genes in this panel are involved in cytokine and interleukin signaling and regulation, hematopoiesis, and activation of the innate and/or adaptive immune response (Stasia and Li. 2008. PubMed ID: 18509647; Picard et al. 2010. PubMed ID: 21057262; Qu et al. 2011. PubMed ID: 21330176; Bustamante et al. 2014. PubMed ID: 25453225; Kreins et al. 2015. PubMed ID: 26304966; Okada et al. 2015. PubMed ID: 26160376; Boisson et al. 2017. PubMed ID: 28597146; Alazami et al. 2018. PubMed ID: 29479355; Donadieu et al. 2018. PubMed ID: 29724903; Gruber et al. 2020. PubMed ID: 32750333). Only about half of the individuals with MSMD have an identified genetic etiology. Subtypes are based upon several features including the impact of the variant, the mode of inheritance, the expression of the mutant allele, and the function affected (Bustamante et al. 2014. PubMed ID: 25453225).

Null variants in IFNGR1 and IFNGR2 are associated with severe forms of MSMD (Qu et al. 2011. PubMed ID: 21330176; Bustamante et al. 2011. PubMed ID: 21278736). Pathogenic variants in IKBKG (aka NEMO) and CYBB have been associated with X-linked forms of MSMD (Filipe-Santos et al. 2006. PubMed ID: 16818673; Qu et al. 2011. PubMed ID: 21330176; Bustamante et al. 2011. PubMed ID: 21278736). The other genetic causes of MSMD included in this panel have variable disease severity (however typically less severe than variants in IFNGR1 and IFNGR1) and inheritance patterns (Bousfiha et al. 2018. PubMed ID: 29226301; Picard et al. 2018. PubMed ID: 29226302; Tangye et al. 2020. PubMed ID: 31953710).

See the individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

Due to the genetic heterogeneity and low incidence of MSMD, the clinical sensitivity of this specific grouping of genes is difficult to estimate. However, it has been estimated that the frequencies of variants in genes associated with MSMD is <1 per million and only about half of individuals with MSMD have an identified genetic etiology (Qu et al. 2011. PubMed ID: 21330176; Bustamante et al. 2014. PubMed ID: 25453225).

For their review, Bustamante compiled a cohort of 406 patients with MSMD (Bustamante et al. 2014. PubMed ID: 25453225). The breakdown in this cohort by gene for causative variants was IL12RB1 (44%), IFNGR1 (29%), IL12B (12%), and IFNGR2 (5%). Variants in CYBB, IRF8, ISG15, IKBKG (aka NEMO), and STAT1 were identified in 4% or less of the cohort.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 96.0% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome CustomPanels).