# Genome-Wide Dissection of Mendelian Susceptibility to Mycobacterial Disease

> **NIH NIH R37** · ROCKEFELLER UNIVERSITY · 2020 · $423,750

## Abstract

Mendelian susceptibility to mycobacterial disease (MSMD) is a primary immunodeficiency syndrome
characterized by severe disease caused by weakly virulent mycobacteria, such as BCG vaccines and
environmental mycobacteria, in otherwise healthy patients. Patients with MSMD are also vulnerable to
tuberculosis and salmonellosis, though other infections are rare. First described clinically in the 1950s, the
pathogenesis of MSMD remained unclear until 1996, when its first genetic etiology was deciphered in
children with interferon-y receptor 1 (IFN-yRI) deficiency. Genetic dissection of MSMD over the last 18 years
has identified 9 morbid genes, including 7 autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, IRF8,
ISG15) and 2 X-linked (NEMO, CYBB) genes. The high level of allelic heterogeneity at these loci has led to
the definition of 18 distinct disorders. The pathogenesis of MSMD in patients with these disorders involves
impaired interleukin-12 (IL-12)-dependent IFN-y immunity. However, only about half of the 700 patients
tested in our lab carried any of these genetic defects. We hypothesize that MSMD in other patients results
from other monogenic inborn errors of immunity, possibly but not necessarily involving the I L - 1 2 - I F N - Y
circuit. We aim to identify new MSMD-causing genes by following a hypothesis-free, genome-wide (GW)
approaches, based on X-linked mapping for defects in X-linked genes, homozygosity mapping for defects in
autosomal genes, and whole-exome sequencing (WES) for other novel MSMD-causing defects. Our
discoveries neatly illustrate the power of GW approaches, particularly WES. From a basic biological
standpoint, this research will provide considerable and novel insights into the mechanisms of immunity to
mycobacteria. Elucidation of the molecular genetic basis of MSMD will also shed light on the pathogenesis of
mycobacterial disease, making it possible to provide molecular diagnoses for patients and genetic
counseling for families. This new information will pave the way for the use of IFN-y or other cytokines for the
treatment of mycobacterial diseases, in addition to antibiotics. Finally, the genetic dissection of MSMD will
pave the way for the genetic dissection of severe tuberculosis in otherwise healthy children.
RELEVANCE (See instructions):
The known genetic etiologies of Mendelian susceptibility to mycobacterial disease (MSMD) impair interferon
(IFN)-v-mediated immunity. Nearly half the patients with MSMD lack a genetic etiology. We hypothesize that
MSMD in these patients also results from inborn errors of immunity, which we aim to identify using
hypothesis-free, GW approaches.

## Key facts

- **NIH application ID:** 9924243
- **Project number:** 5R37AI095983-10
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Jean-Laurent Casanova
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2011-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924243

## Citation

> US National Institutes of Health, RePORTER application 9924243, Genome-Wide Dissection of Mendelian Susceptibility to Mycobacterial Disease (5R37AI095983-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9924243. Licensed CC0.

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