The genetic landscape of severe combined immunodeficiency in the United States and Canada in the current era (2010-2018)

Abstract

Short Summary: In a 250 patient cohort from the US and Canada in the current era (2010–2018), we show that over 90% of patients with severe combined immunodeficiency (SCID) can be genetically-characterized.

Genetic diagnosis of primary immunodeficiencies: A survey of the French national registry

“…This finding is in line with the genetic diagnosis of SCID in the United States, with as many as 90% of 250 patients during the 2010-2018 period. 3 The United States Immunodeficiency Network registry encompasses 5185 patients, 2818 (54.3%) of whom did not have a genetic diagnosis (https://usidnet.org/registry-data/stats-registry-enrollment/; last accessed December 6, 2018).…”

“…Jean-Philippe Jais, MD, PhD a,c,d,e Alain Fischer, MD, PhD a,b,e,g and the members of the CEREDIH French PID study group* 1 The mouse model of RAC2 deficiency and patients with the dominant negative RAC2 D57N mutant have neutrophilia, recurrent abscesses, and defective wound healing. 2,3 Because of the contribution of RAC2 to the function of the glyceraldehyde-3-phosphate dehydrogenase oxidase complex, RAC2 D57N impairs the generation of superoxide in neutrophils. RAC2 D57N also disrupts the polymerization of filamentous actin, thereby reducing myeloid cell and lymphocyte chemotaxis and adhesion.…”

“…RAC2 D57N also disrupts the polymerization of filamentous actin, thereby reducing myeloid cell and lymphocyte chemotaxis and adhesion. 2,3 Although conditional deletion of either RAC1 or RAC2 in lymphocytes is sufficient for intact T-cell and B-cell development in mice, reduced numbers of CD4 1 T cells and B cells have been found in one patient with RAC2 D57N and in another kindred lacking RAC2 protein expression due to a homozygous RAC2 W56X mutation. 4,5 Somatic activating variants in RAC2 have been associated with melanoma, 1 but there are no published reports of germline gain-of-function mutations in any RAC family members.…”

Intact B-Cell Signaling and Function With Host B-Cells 47 Years After Transplantation for X-SCID

“…Severe Combined Immunodeficiency (SCID) is a collection of life-threatening diseases characterized by an absence of functional T cells and requiring treatment with hematopoietic stem cell transplantation (HSCT), gene therapy, or enzyme replacement therapy. At least 70 SCID patients born yearly in the United States and Canada undergo definitive treatment (1,2). Over the past 10 years, the addition of T-cell receptor excision circle (TREC) assays to the newborn screen has allowed for earlier diagnosis, therapy, and improved survival for patients with SCID (3).…”

“…The most common genetic defects resulting in SCID are IL-2 receptor gamma (IL2RG) gene variants causing X-linked SCID (X-SCID) (2). This gene encodes the common gamma chain (γc), which is a subunit of the IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors.…”