Novel genetic variants of inborn errors of immunity

Abstract

Objectives Inborn errors of immunity (IEI) are prevalent in tribal cultures due to frequent consanguineous marriages. Many of these disorders are autosomal recessive, resulting from founder mutations; hence they are amenable to prevention. The primary objective of this study was to evaluate the pathogenicity of novel variants of IEI found among Emiratis. Methods This retrospective data collection study reports novel variants of IEI detected by diagnostic exome sequencing. Pathogenicity prediction was based on scoring tools, amino acid alignment, and Jensen–Shannon divergence values. Results Twenty-one novel variants were identified; nine were frameshift, three nonsense, four intronic (one pathogenic), and five missense (two pathogenic). Fifteen variants were likely pathogenic, of which 13 were autosomal recessive and two uncertain inheritance. Their clinical spectra included combined immunodeficiency, antibody deficiency, immune dysregulation, defects in intrinsic/innate immunity, and bone marrow failure. Conclusion The described novel pathogenic variants are core to a planned national screening program that aims toward IEI prevention. Future studies, however, are needed to confirm their natural history in individual patients and estimate their prevalence in the community.

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

“…Finding novel variants in a known gene, especially if classified with an uncertain significance, may require additional investigations to prove their association with specific phenotypic patterns [28], that is, more than mere in silico predictions [48,49]. The effect of some variants of the CASP10 and PIK3CD genes, found in patients showing symptoms and laboratory alterations similar to ALPS patients (the so-called ALPS undefined, or ALPS-U), but not fully matching the 2009 NIH revised diagnostic criteria [11], was investigated through proper functional tests, allowing confirmation of their postulated pathogenicity [34,44,45].…”

Case Report: BCG-Triggered Hemophagocytic Lymphohistiocytosis in an Infant With X-Linked Recessive Mendelian Susceptibility to Mycobacterial Disease Due to a Variant of Chronic Granulomatous Disease

“…More importantly, "parents should be well-informed and counseled that sharing critical information with the vaccination providers is essential." These preliminary measures are easy to implement, while awaiting wise policies on BCG vaccination (27)(28)(29).…”

“…We conclude that “BCG vaccine should be deferred until required precautions are legitimately dismissed.” In addition, the “electronic health systems” should alert vaccination providers that “There should be no contraindication to the live vaccination before a dose can be requested.” More importantly, “ parents should be well-informed and counseled that sharing critical information with the vaccination providers is essential .” These preliminary measures are easy to implement, while awaiting wise policies on BCG vaccination ( 27 – 29 ).…”

Case Report: Reactive Lymphohistiocytic Proliferation in Infant With a Novel Nonsense Variant of IL2RG Who Received BCG Vaccine

“…Thus, this monogenic inherited condition provides an additional insight into the known list of MSMD (Mendelian susceptibility to mycobacterial diseases) ( 1 – 3 ). This report also advocates for modifying the current practice of early use of BCG ( 8 – 10 ).…”

“…This brief report gives another example on the adverse events of BCG vaccination in a young infants with severe combined immunodeficiency due to a novel variant of IL2RG. It advocates for modifying its use worldwide (6)(7)(8)(9)(10).…”