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STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder. ispartof: J Exp Med vol:220 issue:5 pages:e20221755- ispartof: location:United States status: published

We describe two unrelated patients with inherited IFNAR1 deficiency who suffered from life-threatening infections following measles or yellow fever virus vaccination and were otherwise healthy., Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients’ fibroblast phenotypes are rescued with WT IFNAR1. Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.

Charcot-Marie-Tooth disease (CMT) is the most common hereditary neuropathy of the peripheral nervous system with a wide range of severity and age of onset. CMT patients share similar phenotypes which make it often impossible to identify the disease types based on clinical presentation and electrophysiological studies alone. In recent years, novel genetic diagnostic approaches such as whole exome sequencing (WES) has provided a ground for accurate diagnosis of CMT through identification of the disease-causing mutation(s). In the present study, that approach was effectively employed. Two unrelated large pedigrees with multiple affected cases of various pattern of inheritance (one autosomal dominant and one X-linked) were included. Clinical and electrophysiological data were obtained. DNA sample from each pedigree’s proband was subjected to WES. Data analysis was performed using an in-house developed pipeline, adopted from GATK and ANNOVAR. Candidate variant segregation was evaluated by PCR-based Sanger sequencing. A known but extremely rare (unreported in the Middle Easterners) mutation in BSCL2 (c.C269T:p.S90L) as well as a novel hemizygous variant in GJB1 (c.G224C:p.R75P) were identified and segregations were confirmed by Sanger sequencing. This study supports effectiveness of WES for genetic diagnosis of CMT in undiagnosed families.

The prevalence of primary immunodeficiency (PID) is rather high in Iran compared to the world average, mainly due to the high rate of consanguineous marriage. Despite that, little genetic information is available about primary immunodeficiencies in Iran. Autosomal recessive hyper IgE syndrome (AR-HIES) is a severe type of immunodeficiency, mainly caused by mutations in the dedicator of cytokinesis 8 (DOCK8). Rapid and precise diagnoses of patients suffering from AR-HIES can help to manage the patients and reach properly the treatment decision. However, in regions with low financial resources and limited expertise, deep phenotyping is uncommon. Therefore, an exome-first approach is helpful to make a genetic-based diagnosis. In the present study, whole-exome sequencing (WES) was applied to detect causative mutations in three unrelated primary immunodeficient patients with poor clinical information. One of the cases was a deceased patient with suspected hyper IgE syndrome (HIES) whose parents were subjected to WES. As a result, three novel pathogenic variants were detected in the DOCK8 gene, including two splicing sites (c.4241+1G>T and c.4886+1G>T) and one-stop-gain (c.4201G>T, p.Glu1401Ter) variants. Sanger sequencing confirmed the mutations' segregation in corresponding families. Further immunological investigations confirmed that HIES in the studied probands. The presence of frontal bossing and broad nose in one of the studied cases, in addition to the typical clinical presentation of DOCK8-AR-HIES, is notable. This work suggests that an exome-first approach can be a valuable alternative strategy for precise diagnosis of primary immunodeficiency patients. ispartof: IRANIAN JOURNAL OF ALLERGY ASTHMA AND IMMUNOLOGY vol:19 issue:2 pages:193-199 ispartof: location:Iran status: published

Severe combined immunodeficiency (SCID) comprises a heterogeneous group of genetic disorders caused by early defects in the development and function of T cells. Other lymphocyte lineages (B and/or natural killer cells) are variably affected. With a worldwide frequency of approximately 1:50,000 live births, SCID may result from diverse mutations in over 16 genes. Whole-exome sequencing (WES) provides an opportunity for parallel screening of all those genes. This approach is also useful for genetic diagnosis in parents whose infant expired before genetic testing. Here, we describe a heterozygous novel non-frameshift deletion (c.587_598del p.196_199del) in the adenosine deaminase (ADA) gene identified by WES in healthy parents of an expired child with SCID. The mutation was subsequently confirmed to be homozygous in the deceased baby whose left-over blood sample volume was insufficient for direct WES analysis. In conclusion, we here describe a novel mutation in ADA, a well-known SCID gene. ispartof: IRANIAN JOURNAL OF ALLERGY ASTHMA AND IMMUNOLOGY vol:19 issue:1 pages:94-101 ispartof: location:Iran status: published

Hypomorphic IKBKG mutations in males are typically associated with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Some mutations cause immunodeficiency without EDA (NEMO-ID). The immunological profile associated with these NEMO-ID variants is not fully documented. We present a 2-year-old patient with suspected immunodeficiency in which a hemizygous p.Glu57Lys IKBKG variant was identified. At the age of 1 year, he had an episode of otitis media that evolved into a bilateral mastoiditis (Pseudomonas spp). Hypogammaglobulinemia, specific (polysaccharide) antibody deficiency, and low switched memory B cell subsets were noticed. The mother was heterozygous for the variant but had no signs of incontinentia pigmenti. Patient peripheral blood mononuclear cells produced low amounts of IL-6 after stimulation with IL-1β, Pam3CSK4, and FSL-1. In patient fibroblasts, IκB-α was degraded normally upon stimulation with IL-1β or TNF-α. Transduction of wild-type and variant NEMO in NEMO-/- deficient SV40 fibroblasts revealed a slight but significant reduction of IL-6 production upon stimulation with IL-1β and TNF-α. In conclusion, we demonstrated that p.Glu57Lys leads to specific immunological defects in vitro. No other pathogenic PID variants were identified through whole exome sequencing. As rare polymorphisms have been described in IKBKG and polygenic inheritance remains an option in the presented case, this study emphasizes the need for thorough functional and genetic evaluation when encountering and interpreting suspected disease-causing NEMO-ID variants.

Background Congenital heart disease (CHD) is the most common birth defect and a major health problem around the world. However, its exact etiology has remained unclear. Among various genetic contributing factors, GATA4 transcription factor plays a significant role in the CHD pathogenesis. In this study, GATA4 coding sequence was screened in Iranian patients of various ethnicities. Methods Sixty six individuals with familial CHD referred to our center were recruited in this study. After receiving written informed consent from each individual or their parents, chromosomal analyses and GATA4 variant screening were performed. Pathogenicity of the suspected variants was evaluated using available online software tools: CADD, Mutation Taster, SIFT, and PolyPhen‐2. Results A total of twelve GATA4 variants were detected including five intronic, 2 exonic and 3 polymorphisms as well as 2 missense mutations, the c.1220C>A and c.1309G>A. Unlike the c.1220C>A, the likely pathogenic heterozygous c.1309G>A has not been previously associated with any phenotype. Here, we not only report, for the first time, a c.1309G>A‐related CHD, but also report a novel de novo balanced translocation, 46,XY,t(5;7)(qter13;qter11), in the same patient which may have influenced the disease severity. Conclusion From screening GATA4 sequence in 66 Iranian patients of various ethnicities, we conclude that cytogenetic analysis and PCR‐direct sequencing of different candidate genes may not be the best approach for genetic diagnosis in CHD. Applying novel approaches such as next‐generation sequencing (NGS) may provide a better understating of genetic contributing factors in CHD patients for whom conventional methods could not reveal any genetic causative factor.

ispartof: JOURNAL OF CLINICAL IMMUNOLOGY vol:39 issue:2 pages:138-141 ispartof: location:Netherlands status: published

Osteosclerotic metaphyseal dysplasia (OSMD) is a very rare autosomal-recessive disorder and a distinctive type of osteopetrosis, characterized mainly by skeletal fractures and deformity, osteosclerosis, and sometimes hypotonia, developmental delay, and seizures. Sequence variants in the leucine-rich repeat kinase 1 (LRRK1) gene underlying OSMD have been reported previously. In the present study, we investigated a 14-year-old girl suspected with OSMD in a consanguineous family of Iranian origin segregating the disease in an autosomal-recessive manner. The patient had severe short stature, multiple sclerotic lesions, sandwich vertebrae, Erlenmeyer flask deformity, and looser zones. The multifocal active bony pathology suggested multifocal bony inflammation or multiple looser fractures. Whole-exome sequencing followed by Sanger sequencing confirmation revealed a novel homozygous stop gain mutation (c.G2785T, p.E929X) in the LRRK1 gene. This is the first mutation in the LRRK1 gene, underlying OSMD, in the Iranian population and the third case worldwide. The mutation is located in the C terminal of the Roc domain, distinct from domains affected in the previous two LRRK1 mutations. Additionally, a new group of clinical indications different from the two previous cases is discussed.

The draft genome sequence of Pseudomonas gingeri LMG 5327 (NCPPB 3146), the causative agent of ginger blotch in Agaricus bisporus , is reported. Together with another mushroom pathogen, Pseudomonas agarici , it belongs to a distinct phylogenomic group.

Genetic contributing factors to non-syndromic hearing loss (NSHL) are remarkably diverse spanning over autosomal to X-linked to mitochondrial inheritance patterns. Facing a quite unconventional pedigree, here we report implementation of whole exome sequencing (WES) to uncover mitochondrial pathogenic variant in a six-generation Iranian family with four cases affected with hereditary NSHL of variable severity. As a result, heteroplasmic transition of A to G at position 1555 of MT-RNR1 gene was identified in all affected individuals co-existing with nuclear c.28G > T (p.A10S) variant in the TRMU gene, only in some patients. The reliability of WES to infer nuclear as well as mitochondrial variants in hearing loss were discussed.