Case report and review of the literature: immune dysregulation in a large familial cohort due to a novel pathogenic RELA variant.

OBJECTIVE: To explore and define the molecular cause(s) of a multi-generational kindred affected by Bechet's-like mucocutaneous ulcerations and immune dysregulation. METHODS: Whole genome sequencing and confirmatory Sanger sequencing were performed. Components of the NFκB pathway were quantified by immunoblotting, and function was assessed by cytokine production (IL-6, TNF-α, IL-1ß) after lipopolysaccharide (LPS) stimulation. Detailed immunophenotyping of T-cell and B-cell subsets was performed in four patients from this cohort. RESULTS: A novel variant in the RELA gene, p. Tyr349LeufsTer13, was identified. This variant results in premature truncation of the protein before the serine (S) 536 residue, a key phosphorylation site, resulting in enhanced degradation of the p65 protein. Immunoblotting revealed significantly decreased phosphorylated [p]p65 and pIκBα. The decrease in [p]p65 may suggest reduced heterodimer formation between p50/p65 (NFκB1/RelA). Immunophenotyping revealed decreased naïve T cells, increased memory T cells, and expanded senescent T-cell populations in one patient (P1). P1 also had substantially higher IL-6 and TNF-α levels post-stimulation compared with the other three patients. CONCLUSION: Family members with this novel RELA variant have a clinical phenotype similar to other reported RELA cases with predominant chronic mucocutaneous ulceration; however, the clinical phenotype broadens to include Behçet's syndrome and IBD. Here we describe the clinical, immunological and genetic evaluation of a large kindred to further expand identification of patients with autosomal dominant RELA deficiency, facilitating earlier diagnosis and intervention. The functional impairment of the canonical NFκB pathway suggests that this variant is causal for the clinical phenotype in these patients.

Paediatric asthma - all that wheezes is not necessarily asthma - current diagnostic and management strategies.

PURPOSE OF REVIEW: Asthma is a frequently encountered chronic medical condition encountered in paediatrics, affecting 7% of children under the age of 18 in the United States. Although asthma is one of the more common conditions that is associated with wheezing, there is a broad differential diagnosis to consider. The purpose of this review is to describe other causes of wheezing outside of asthma in a paediatric population and discuss diagnostic and management strategies to consider when evaluating a child or adolescent with wheezing. RECENT FINDINGS: The characteristics of the wheezing along with other associated signs and symptoms can be helpful in narrowing the differential diagnosis. The age and the past medical history of the patient are also important aspects to consider when determining next steps in the evaluation and management of paediatric wheezing. In addition to considering other causes of wheezing, it is often necessary to assess for the presence of underlying asthma, and recently updated asthma guidelines from the National Heart, Lung and Blood Institute provide a graded review of various recommendations for making the diagnosis and managing asthma in the clinical setting. SUMMARY: It is important to maintain a broad differential diagnosis when evaluating a paediatric patient with wheezing.

A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20.

Congenital heart defects involving left-sided lesions (LSLs) are relatively common birth defects with substantial morbidity and mortality. Previous studies have suggested a high heritability with a complex genetic architecture, such that only a few LSL loci have been identified. We performed a genome-wide case-control association study to address the role of common variants using a discovery cohort of 778 cases and 2756 controls. We identified a genome-wide significant association mapping to a 200 kb region on chromosome 20q11 [P= 1.72 × 10-8 for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 × 10-9, odds ratio (OR)= 1.6 for both]. This result was supported by transmission disequilibrium analyses using a subset of 541 case families (lowest P in region= 4.51 × 10-5, OR= 1.5). Replication in a cohort of 367 LSL cases and 5159 controls showed nominal association (P= 0.03 for rs3746446) resulting in P= 9.49 × 10-9 for rs3746446 upon meta-analysis of the combined cohorts. In addition, a group of seven SNPs on chromosome 1q21.3 met threshold for suggestive association (lowest P= 9.35 × 10-7 for rs12045807). Both regions include genes involved in cardiac development-MYH7B/miR499A on chromosome 20 and CTSK, CTSS and ARNT on chromosome 1. Genome-wide heritability analysis using case-control genotyped SNPs suggested that the mean heritability of LSLs attributable to common variants is moderately high ([Formula: see text] range= 0.26-0.34) and consistent with previous assertions. These results provide evidence for the role of common variation in LSLs, proffer new genes as potential biological candidates, and give further insight to the complex genetic architecture of congenital heart disease.