BackgroundThe genetic cause of primary immunodeficiency disease (PID) carries prognostic information.ObjectiveWe conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource–Rare Diseases cohort.MethodsIn the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses.ResultsBoth sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases.ConclusionWe show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

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Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability.

The effects of oral administration of linoleic- and γ-inolenic-acid-rich oils on the clinical and histopathological manifestations of experimental autoimmune encephalomyelitis (EAE) were investigated in Lewis rats 7 d post-inoculation. γ-Linolenic-acid-rich fungal (Mucor javanicus) oil at 500 mg/kg body weight abrogated clinical and histological signs of EAE although at doses of 200 and 1000 mg/kg body weight it was only effective in delaying the onset of clinical disease. Linoleic-acid-rich safflower-seed (Carthamus tinctorius) oil at 500, 750 and 1000 mg/kg body weight decreased the severity of clinical EAE. disease in a dose-dependent manner. The effects in healthy animals of orally administered γ-linolenic-acid-rich fungal oil (500 mg/kg body weight) and linoleic-acid-rich safflower-seed oil (1000 mg/kg body weight) on splenic lymphocyte proliferative responses to the T-cell mitogen concanavalin-A (Con A), membrane fatty acid composition and lymphocyte sub-sets were also studied. Both treatments enhanced the T-cell proliferative response to Con A. There was no significant effect on the proportion of splenic CD8+ or CD4+ lymphocytes. Compositional studies on splenic phosphoglyceride fatty acids of oil-treated animals suggest the above responses were associated with increases in spleen dihomo-γ-linolenic and arachidonic acids.