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Notice of Special Interest (NOSI): Molecular and Genetic Characterization of Inborn Errors of Immunity

National Institutes of Health

The purpose of this Notice of Special Interest (NOSI) is to advance the experimental validation and functional characterization of genetic variants in coding or non-coding genomic regions that result in inborn errors of immunity/primary immunodeficiency diseases and to elucidate the molecular, cellular, and immunological mechanisms of these disorders. Understanding the genetic basis of primary immunodeficiency disorders is essential for their diagnosis, prognosis, and the development of precision therapeutics.

Inborn errors of immunity/primary immunodeficiency diseases result largely from inherited genetic defects that perturb immune regulation or function; they are often severe in nature; and are characterized by highly diverse phenotypes such as infection, autoimmunity, auto-inflammation, allergy, and malignancy. Genomic analysis and experimental validation of genetic variants have been instrumental in the identification of numerous inborn errors of immunity/primary immunodeficiencies to date. More than 400 inborn errors of immunity have been identified in both coding and non-coding regions of the genome, as noted in the "Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082301/ .

In silico prediction models suggest that mutations in more than 3000 coding regions may cause hitherto unrecognized inborn errors of immunity, while numerous mutations in non-coding regions also are expected to cause disease, underlining the public health significance in understanding the genetic basis of primary immunodeficiency disorders and reinforcing the notion that hundreds to thousands of these disorders remain unidentified. Furthermore, since these disorders are characterized by a high degree of phenotypic heterogeneity, understanding their genetic basis is essential for appropriate diagnosis, prognosis, and treatment.

The biochemical and functional characterization of genetic defects discovered through genomic investigation enabled not only the molecular characterization of numerous known and novel inborn errors of immunity but, importantly, also revealed defects in immunoregulatory pathways responsible for the disease phenotype. Significantly, the molecular diagnosis of inborn errors of immunity/primary immunodeficiency diseases has paved the way for the development of precision medicine therapeutics.

This notice applies to due dates on or after February 5, 2022 , and subsequent receipt dates through January 7, 2025 .

NOT-AI-21-082