NIH/NIAID – Molecular and Genetic Characterization of Inborn Errors of Immunity (R01, R21 Clinical Trial Not Allowed)

December 3, 2018 by School of Medicine Webmaster

The following description was taken from the R01 version of the FOA.

The purpose of this FOA is to advance the experimental validation and functional characterization of genetic variants (coding or non-coding) 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 350 inborn errors of immunity have been identified, as noted by the International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity, in both coding and non-coding regions of the genome.

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 are also 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 it 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.

Research Objectives and Scope

Research areas supported by this FOA include, but are not limited to, the experimental validation and immunological characterization of:

  • Single nucleotide variants (inherited or de novo) in coding or non-coding regions of the genome that cause inborn errors of immunity;
  • Insertions or deletions (indels) in coding or non-coding regions of the genome that cause inborn errors of immunity;
  • Digenic/polygenic mutations that cause inborn errors of immunity;
  • Structural variations (large insertions or deletions, translocations, inversions, or copy-number variations) that cause inborn errors of immunity.

State-of-the-art technologies and approaches (e.g., iPSC technology, CRISPR/Cas9 gene editing, multi-omics such as transcriptomics, proteomics, epigenetics etc) used to accomplish the objectives of this FOA are strongly encouraged.

The prioritization of putative disease-causing variant(s) is expected to be finalized by the time applications are submitted. For the genetic variant(s) that are chosen to be investigated further according to the objectives of this FOA, preliminary data should be presented to support causality between the variant(s) and disease phenotype.

The clinical and laboratory phenotype of the patients should be well defined and relevant medical history should be available. Information about the patient cohort(s) or family pedigree(s) should be provided. For single patient studies, adherence to the guidelines established for genetic studies in single patients is strongly encouraged.

Utilization of relevant cell types isolated from the patient(s) and appropriate controls (e.g., unaffected family members, healthy subjects of the same ethnic origin etc.) are strongly encouraged for the delineation of the functional consequences of the mutations under investigation. If animal models are used to elucidate the mechanism of disease, a clear correlation between human and animal disease phenotypes should be established. In all cases, preliminary data should demonstrate that the genotype/phenotype correlation recapitulates the patient’s clinical disease.

This FOA will NOT support

  • Studies that propose the use of targeted gene sequencing panels, which analyze specific mutations known to cause inborn errors of immunity/primary immunodeficiency diseases, since they will not aid in the identification of novel disease-causing mutations;
  • Characterization of somatic mutations;
  • Phenocopies of inborn errors of immunity/primary immunodeficiency diseases;
  • Applications that focus on HIV/SIV/AIDS.

Deadlines:  standard dates apply


Filed Under: Funding Opportunities