Comprehensive Genetic Results for Primary Immunodeficiency Disorders in a Highly Consanguineous Population

Objective: To present the genetic causes of patients with primary immune deficiencies (PIDs) in Kuwait between 2004 and 2017.Methods: The data was obtained from the Kuwait National Primary Immunodeficiency Disorders Registry. Genomic DNA from patients with clinical and immunological features of PID was sequenced using Sanger sequencing (SS), next generation sequencing (NGS) of targeted genes, whole exome sequencing (WES), and/or whole genome sequencing (WGS). Functional assays were utilized to assess the biologic effect of identified variants. Fluorescence in situ hybridization (FISH) for 22q11.2 deletion and genomic hybridizations arrays were performed when thymic defects were suspected.Results: A total of 264 patients were registered during the study period with predominance of patients with immunodeficiencies affecting cellular and humoral immunity (35.2%), followed by combined immunodeficiencies with associated syndromic features (24%). Parental consanguinity and family history suggestive of PID were reported in 213 (81%) and 145 patients (55%), respectively. Genetic testing of 206 patients resulted in a diagnostic yield of 70%. Mutations were identified in 46 different genes and more than 90% of the reported genetic defects were transmitted by in an autosomal recessive pattern. The majority of the mutations were missense mutations (57%) followed by deletions and frame shift mutations. Five novel disease-causing genes were discovered.Conclusions: Genetic testing should be an integral part in the management of primary immunodeficiency patients. This will help the delivery of precision medicine and facilitate proper genetic counseling. Studying inbred populations using sophisticated diagnostic methods can allow better understanding of the genetics of primary immunodeficiency disorders

Autosomal recessive agammaglobulinemia - first case with a novel TCF3 mutation from Pakistan

Autosomal Recessive Agammaglobulinemia (ARA) is an uncommon type of primary immunodeficiency characterized by mutations in genes responsible for early B cell differentiation and function. One such gene is the TCF3 gene, which encodes a transcription factor important for immunoglobulin gene expression. We present the case of a 9 year old girl with history of diarrhea and recurrent pneumonias. Laboratory investigation showed significantly reduced levels of immunoglobulins along with a significant fall in the number of CD19+ cells. Genetic analysis identified a TCF3 gene base deletion covering exons 5-11

Multi-kingdom ecological drivers of microbiota assembly in preterm infants

The preterm infant gut microbiota develops remarkably predictably(1–7), with pioneer species colonizing after birth, followed by an ordered succession of microbes. The gut microbiota is vital to preterm infant health(8,9) yet the forces underlying these predictable dynamics remain unknown. The environment, the host, and microbe-microbe interactions are all likely to shape microbiota dynamics, but in such a complex ecosystem identifying the specific role of any individual factor has remained a major challenge(10–14). Here we use multi-kingdom absolute abundance quantitation, ecological modelling, and experimental validation to overcome this challenge. We quantify the absolute bacterial, fungal, and archaeal dynamics in a longitudinal cohort of 178 preterm infants. We uncover, with exquisite precision, microbial blooms and extinctions and reveal an inverse correlation between bacterial and fungal loads in the infant gut. We infer computationally and demonstrate experimentally in vitro and in vivo that predictable assembly dynamics may be driven by directed, context-dependent interactions between specific microbes. Mirroring the dynamics of macroscopic ecosystems(15–17), a late-arriving member, Klebsiella, exploits the pioneer, Staphylococcus, to gain a foothold within the gut. Remarkably, we find that interactions between kingdoms can influence assembly, with a single fungal species, Candida albicans, inhibiting multiple dominant gut bacteria. Our work unveils the centrality of simple microbe-microbe interactions in shaping host-associated microbiota, critical for both our understanding of microbiota ecology and targeted microbiota interventions

A novel mutation in the JH4 domain of JAK3 causing severe combined immunodeficiency complicated by vertebral osteomyelitis

JAK3 is a tyrosine kinase essential for signaling downstream of the common gamma chain subunit shared by multiple cytokine receptors. JAK3 deficiency results in T-B+NK- severe combined immune deficiency (SCID). We report a patient with SCID due to a novel mutation in the JAK3 JH4 domain. The function of the JH4 domain remains unknown. This is the first report of a missense mutation in the JAK3 JH4 domain, thereby demonstrating the importance of the JH4 domain of JAK3 in host immunity

Atypical phenotype of an old disease or typical phenotype of a new disease: deficiency of adenosine deaminase 2

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder caused by mutations in CECR1 (cat eye syndrome chromosome region, canditate 1) gene, which encodes the enzyme adenosine deaminase 2 necessary for endothelial cell survival and function

Human primary immunodeficiency caused by expression of a kinase-dead p110δ mutant

This case demonstrates the essential contribution of the p110δ catalytic 21 domain in adaptive immunity function in a patient with expression of a kinase-dead p110δ mutant

Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex

The coat protein I (COPI) complex mediates retrograde trafficking from the Golgi to the endoplasmic reticulum (ER). Five siblings with persistent bacterial and viral infections and defective humoral and cellular immunity had a homozygous p.K652E mutation in the γ1 subunit of COPI (γ1-COP). The mutation disrupts COPI binding to the KDEL receptor and impairs the retrieval of KDEL-bearing chaperones from the Golgi to the ER. Homozygous Copg1K652E mice had increased ER stress in activated T and B cells, poor antibody responses, and normal numbers of T cells that proliferated normally, but underwent increased apoptosis upon activation. Exposure of the mutants to pet store mice caused weight loss, lymphopenia, and defective T cell proliferation that recapitulated the findings in the patients. The ER stress-relieving agent tauroursodeoxycholic acid corrected the immune defects of the mutants and reversed the phenotype they acquired following exposure to pet store mice. This study establishes the role of γ1-COP in the ER retrieval of KDEL-bearing chaperones and thereby the importance of ER homeostasis in adaptive immunity.11Nsciescopu

Recurrent Viral Infections Associated with a Homozygous Coro1A Mutation That Disrupts Oligomerization and Cytoskeletal Association

Background: Coronin-1A (CORO1A) is a regulator of actin dynamics important for T-cell homeostasis. CORO1A deficiency causes T-B+ natural killer-positive severe combined immunodeficiency or T-cell lymphopenia with severe viral infections. However, because all known human mutations in CORO1A abrogate protein expression, the role of the protein's functional domains in host immunity is unknown. Objective: We sought to identify the cause of the primary immunodeficiency in 2 young adult siblings with a history of disseminated varicella, cutaneous warts, and CD4(+) T-cell lymphopenia. Methods: We performed immunologic, genetic, and biochemical studies in the patients, family members, and healthy control subjects. Results: Both patients had CD4(+) T-cell lymphopenia and decreased lymphocyte proliferation to mitogens. IgG, IgM, IgA, and specific antibody responses were normal. Whole-genome sequencing identified a homozygous frameshift mutation in CORO1A disrupting the last 2 C-terminal domains by replacing 61 amino acids with a novel 91-amino-acid sequence. The CORO1A(S401fs) mutant was expressed in the patients' lymphocytes at a level comparable with that of wild-type CORO1A in normal lymphocytes but did not oligomerize and had impaired cytoskeletal association. CORO1A(S401fs) was associated with increased filamentous actin accumulation in T cells, severely defective thymic output, and impaired T-cell survival but normal calcium flux and cytotoxicity, demonstrating the importance of CORO1A oligomerization and subcellular localization in T-cell homeostasis. Conclusions: We describe a truncating mutation in CORO1A that permits protein expression and survival into young adulthood. Our studies demonstrate the importance of intact CORO1A C-terminal domains in thymic egress and T-cell survival, as well as in defense against viral pathogens.Wo