Functional Genetics in Inborn Errors of Immunity

Abstract

Inborn errors of immunity are genetic defects of the immune system, causing increased susceptibility to infection, autoinflammation, autoimmunity and immune dysregulation. Next-generation sequencing has enabled exponential identification of novel inborn errors of immunity due to mutations in genes encoding for proteins that participate in the immune response. However, genomic sequencing often yields multiple variants in potential candidate genes, hence functional validation of these genetic defects becomes paramount to achieve diagnosis and discovery. Genome-editing technologies such as CRISPR-Cas9 have allowed exponential advances on discovery of new primary immunodeficiencies, enabling appropriate diagnosis and treatment. This review summarizes the heterogeneous clinical presentation of primary immunodeficiencies and contextualizes the rationale for functional validation studies to achieve diagnosis and discovery, subsequently leading to the application of directed therapies.

Recurrent Tumefactive Central Nervous System Lesions Due to BRIP1-Related Fanconi Anemia

“…This manuscript describes a patient with tumefactive CNS lesions caused by a CNS vasculopathy associated with BRIP1 mutation with multisystem complications. Mechanistically, the specific role of BRIP1 mutation in CNS inflammation and vasculopathy is unclear though in general, disorders of immunodeficiency can lead to autoimmunity and/or immune dysregulation due to possible loss or gain of function of components of the immune system 5 . Another consideration is if the development of vasculopathy 9 years after BMT is due to late failure of the transplant or if the brain pathology is due to the patient’s brain cells having the pathogenic variant leading to pathology despite peripheral circulation being from the donor.…”

Inborn Errors of Immunity With Fetal or Perinatal Clinical Manifestations

“…FLH is characterized by functional defects of cytotoxic T lymphocytes and NK cells, and associated with mutations in various genes, being PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5) the most frequently identified so far (3). Patients with some syndromes with hypopigmentation and defective lymphocyte granule-mediated cytotoxicity, such as Griselli syndrome type 2 (due to RAB27A mutations), Chédiak-Higashi syndrome (LYST mutations) and Hermansky-Pudlak syndrome type 2 (AP3B1 mutations) develop HLH, sometimes in early life (44)(45)(46)(47). The X-linked lymphoproliferative diseases (XLP) caused by pathogenic variants of SH2D1A (XLP1) and XIAP (XLP2) can also present with HLH (46).…”

Challenges of Diagnosing Mendelian Susceptibility to Mycobacterial Diseases in South Africa

“…Individuals suffering from IEI are not only predisposed to recurrent and chronic infections-despite completion of appropriate treatment clearing previous infections-but also have an increased risk of developing autoinflammatory, autoimmune, and allergic responses, significantly increasing their morbidity and mortality [4][5][6][7]. Individuals with IEI allow for the unique opportunity to study and understand the function of affected pathways in the human immune system [5].…”

“…In light of this, multiple diagnostic gene panels are currently available to screen for known IEI-associated genes. These panels include between 200 and 407 genes, allowing for the molecular diagnosis of patients to be much more efficient and cost-effective than next-generation sequencing (NGS) technologies [5].…”