Whole-exome sequencing to identify undiagnosed primary immunodeficiency disorders in children with community-acquired sepsis, admitted in the pediatric intensive care unit.

BACKGROUND: Whole-exome sequencing (WES) provides a powerful diagnostic tool for identifying primary immunodeficiency diseases (PIDs). This study explores the utility of this approach in uncovering previously undiagnosed PIDs in children with community-acquired sepsis (CAS), with a medical history of recurrent infections or a family history of PIDs. METHODS: We performed WES on DNA samples extracted from the blood of the 34 enrolled patients, followed by bioinformatic analysis for variant calling, annotation, and prioritization. We also performed a segregation analysis in available family members to confirm the inheritance patterns and assessed the potential impact of the identified variants on protein function. RESULTS: From 34 patients enrolled in the study, 29 patients (85%) with previously undiagnosed genetic diseases, including 28 patients with PIDs and one patient with interstitial lung and liver disease, were identified. We identified two patients with severe combined immunodeficiency (SCID), patients with combined immunodeficiency (CID), six patients with combined immunodeficiency with syndromic features (CID-SF), four patients with defects in intrinsic and innate immunity, four patients with congenital defects of phagocyte function (CPDF), and six patients with the disease of immune dysregulation. Autoinflammatory disorders and predominantly antibody deficiency were diagnosed in one patient each. CONCLUSION: Our findings demonstrate the potential of WES in identifying undiagnosed PIDs in children with CAS. Implementing WES in the clinical evaluation of CAS patients with a warning sign for PIDs can aid in their timely diagnosis and potentially lead to improved patient care.

A novel X-linked mutation in IL2RG associated with early-onset inflammatory bowel disease: a case report of twin brothers.

BACKGROUND: X-linked severe combined immunodeficiency is caused by IL2RG gene mutation. Several variations have been identified in the IL2RG gene, which potentially can prevent the production of nonfunctional proteins. Herein, a novel X-linked variant in the IL2RG gene is reported in twin brothers, associated with inflammatory bowel symptoms. CASE PRESENTATION: The patients were 26-month-old monozygotic twin middle-eastern males with failure to thrive and several inpatient admissions due to severe chronic nonbloody diarrhea that started at the age of 12 months. Pancolitis was revealed after performing upper and lower gastrointestinal endoscopies on the twin with more severe gastrointestinal symptoms. Flow cytometric evaluation of the peripheral blood cells showed low levels of CD4+ cells in both patients. Next generation sequencing-based gene panel test results of the two patients proved a novel heterozygous missense X-linked IL2RG mutation (70330011 A > G, p.Trp197Arg) in one of the patients, which was predicted to be deleterious (CADD score of 28), which soon after was confirmed by Sanger segregation in his twin brother. Both parents were wild types and had never experienced similar symptoms. The patients received an human leukocyte antigen (HLA)-matched cord blood transplant. The twin with more severe gastrointestinal symptoms died 1 month after transplantation. In his brother, watery diarrhea eventually subsided after transplantation. CONCLUSION: Intestinal involvement in X-linked severe combined immunodeficiency is a rare presentation that might be neglected. The increasing availability of genetic screening tests worldwide could be helpful for early detection of such lethal primary immunodeficiency diseases and in implementing effective interventions to handle the severe outcomes.

Severe congenital neutropenia due to G6PC3 deficiency: early and delayed phenotype of a patient.

BACKGROUND: Severe Congenital Neutropenia type 4 (SCN4), is a rare autosomal recessive condition, due to mutations in the G6PC3 gene. The phenotype comprises neutropenia of variable severity and accompanying anomalies. CASE PRESENTATION: We report a male patient with confirmed G6PC3 deficiency presented with recurrent bacterial infections and multi-systemic complications. Our case was the first with a novel homozygous frameshift mutation in G6PC3. The patient demonstrated large platelets on his peripheral blood smear which is a rare presentation of this disease. CONCLUSION: As SCN4 patients could be easily missed, it is recommended to consider G6PC3 mutation for any case of congenital, unexplained neutropenia.

DNAH11 and a Novel Genetic Variant Associated with Situs Inversus: A Case Report and Review of the Literature.

Background: Primary ciliary dyskinesia (PCD), also known as the immotile-cilia syndrome, is a clinically and genetically heterogeneous syndrome. Improper function of the cilia causes impaired mucociliary clearance. Neonatal respiratory distress, rhinosinusitis, recurrent chest infections, wet cough, and otitis media are respiratory presentations of this disease. It could also manifest as infertility in males as well as laterality defects in both sexes, such as situs abnormalities (Kartagener syndrome). During the past decade, numerous pathogenic variants in 40 genes have been identified as the causatives of primary ciliary dyskinesia. DNAH11 (dynein axonemal heavy chain 11) is a gene that is responsible for the production of cilia's protein and encodes the outer dynein arm. Dynein heavy chains are motor proteins of the outer dynein arms and play an essential role in ciliary motility. Case Presentation. A 3-year-old boy, the offspring of consanguineous parents, was referred to the pediatric clinical immunology outpatient department with a history of recurrent respiratory tract infections and periodic fever. Furthermore, on medical examination, situs inversus was recognized. His lab results revealed elevated levels of erythrocyte sedimentation rate (ESR) and C reactive protein (CRP). Serum IgG, IgM, and IgA levels were normal, while IgE levels were elevated. Whole exome sequencing (WES) was performed for the patient. WES demonstrated a novel homozygous nonsense variant in DNAH11 (c.5247G > A; p. Trp1749Ter). Conclusion: We reported a novel homozygous nonsense variant in DNAH11 in a 3-year-old boy with primary ciliary dyskinesia. Biallelic pathogenic variants in one of the many coding genes involved in the process of ciliogenesis lead to PCD.

The burden of childhood and adolescent cancers in North Africa and the Middle East (NAME) region: findings from the Global Burden of Disease study 2019.

INTRODUCTION: Despite the significant burden of childhood and adolescent cancers, no specific studies recently discussed the burden of cancer in this group in the North Africa and the Middle East (NAME) region. Therefore, we aimed to study the burden of cancers in this group in this region. MATERIALS AND METHODS: We retrieved the Global Burden of Disease (GBD) data for children and adolescent cancers (0-19 years old) in the NAME region from 1990 to 2019. 21 types of neoplasms were grouped as "neoplasms", comprising 19 specific cancer groups as well as "other malignant neoplasms" and "other neoplasms". Three significant parameters of incidence, deaths, and Disability-Adjusted Life Years (DALYs) were studied. The data are presented with 95% uncertainty intervals (UI), and reported rates per 100,000. RESULTS: In 2019, almost 6 million (95% UI: 4.166 M-8.405 M) new cases and 11,560(9770-13,578) deaths due to neoplasms occurred in the NAME region. Incidence was higher in females (3.4 M), while deaths (6226 of overall 11,560) and DALYs (501,118 of overall 933,885) were estimated as higher in males. Incidence rates did not significantly change since 1990, while deaths and DALYs rates declined significantly. After excluding "other malignant neoplasms" and "other neoplasms", leukemia was responsible for the highest number of incidence and deaths (incidence: 10,629(8237-13,081), deaths: 4053(3135-5013), followed by brain and central nervous system cancers (incidence: 5897(4192-7134), deaths: 2446(1761-2960)), and non-Hodgkin lymphoma (incidence: 2741 (2237-3392), deaths: 790(645-962)). Incidence rates of neoplasms were similar for most countries, but countries varied more in terms of death rates. Afghanistan 8.9(6.5-11.9), Sudan 6.4(4.5-8.6), and the Syrian Arab Republic 5.6(4.3-8.3) had the highest overall death rates. CONCLUSION: The NAME region is observing relatively constant incidence rates and a decreasing pattern in the deaths and DALYs. Despite this success, several countries are lagging behind in development. Different issues such as economic problems, armed conflicts and political instabilities, lack of equipment or experienced staff or poor distribution, stigmatization and disbelief in the healthcare systems account for unfavorable numbers in some countries. Such problems require urgent solutions as new sophisticated and personalized cares raise the alarm for even more inequalities between high and low-income countries.

Novel DNMT3B Mutation in a Patient with Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome and a Bronchopulmonary Collateral Artery.

BACKGROUND: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder. ICF1 is caused by bi-allelic mutations in the gene encoding deoxyribonucleic acid methyltransferase-3B (DNMT3B). Herein, we report a novel homozygous DNMT3B mutation in a patient with ICF1. CASE PRESENTATION: An eight-month-old Iranian Caucasian infant of consanguineous 1st-degree cousins presented to our clinic for evaluation of neutropenia. Physical examination was unremarkable except for low-set ears and a systolic cardiac murmur. He had a history of recurrent respiratory infections and oral thrush. Moreover, a collateral artery between the bronchial and pulmonary arteries was observed on the angiogram, mimicking a patent ductus arteriosus on the echocardiogram. Growth percentiles were normal; however, he had a neurodevelopmental delay. Family history was significant for a sibling who deceased at nine months of age after recurrent respiratory infections. Laboratory evaluation revealed a normal white blood cell count with neutropenia and normal bone marrow studies. He had hypogammaglobinemia with normal flow cytometric studies and was treated with prophylactic trimethoprim-sulfamethoxazole and itraconazole. After that, he was re-admitted three times due to recurrent episodes of pneumonia and an episode of pseudomonas aeruginosa meningitis. Currently, he is five years old and doing well on monthly intravenous immunoglobulin. Due to recurrent infections, hypogammaglobulinemia, and neutropenia, as well as a family history of consanguinity and a sibling who deceased during infancy, a primary immune deficiency was suspected. Genetic studies utilizing whole-exome sequencing demonstrated a homozygous missense mutation in DNMT3B (LRG_56t1:c.2008C>T; p.Arg670Trp) in the patient studied. The mutation has not been previously reported. CONCLUSION: We describe a novel homozygous DNMT3B mutation in an Iranian boy with ICF1. It is associated with recurrent infections, hypogammaglobinemia, neutropenia, mild facial anomalies, and a bronchopulmonary collateral artery.

Regional and national burden of leukemia and its attributable burden to risk factors in 21 countries and territories of North Africa and Middle East, 1990-2019: results from the GBD study 2019.

PURPOSE: Regional and national data on leukemia's burden provide a better comprehension of leukemia's trends and are vital for policy-makers for better allocation of the resources. This study reports the burden of leukemia, and the attributed burden to its risk factors in 21 countries and territories of the North Africa and Middle East. METHODS: Data from cancer registration, scientific literature, survey, and reports were the input to estimate the burden of leukemia. In addition, the burden of attributable risk factors with evidence of causation with leukemia was calculated using the comparative risk assessment framework. All measures are reported as counts and rates divided by sex and specific age groups. RESULTS: In 2019, there were 39,297 (95% uncertainty interval: 32,617-45,056) incident cases of leukemia with an age-standardized rate (ASR) of 7.8 (6.5-8.8) per 100,000 in the region. There were also 25,143 (21,109-28,826) deaths and 1,011,555 (822,537-1,173,621) DALYs attributed to Leukemia with an ASR of 5.4 (4.6-6.1) per 100,000 and 183.4 (150.7-211.2) per 100,000, respectively. Years of life lost (YLLs) (179.4 [147.2-206.7]) were accountable for the major part of DALYs. All count measures increased, while all the ASRs decreased during 1990-2019. The Syrian Arab Republic, Qatar, and Afghanistan had the highest ASR incidence, mortality, and DALYs rate in 2019. Incidence, DALYs, and prevalence rates were higher in males of all age groups except under five, and the highest rates were observed in +75 age group. Four major risk factors for leukemia were smoking, high body mass index, occupational exposure to benzene, and formaldehyde. CONCLUSION: Despite the reduction in age-standardized rates of incidence and mortality, the burden of leukemia has increased steadily, due to population growth and aging. Notable variations exist between age-standardized rates in region's countries.

The Clinical and Molecular Assessment of Iranian Families with Severe Congenital Neutropenia, Identification of HYOU1 and SHOC2 as Potential Novel Gene Defects.

Neutropenia congenita grave (SCN) is a rare disease with a genetically and clinically heterogeneous nature, usually diagnosed in childhood, with an elevated risk of infections such as otitis, skin infections, pneumonia, deep abscesses, and septicemia. Patients with SCN also have an increased risk of leukemia, and mutations in the ELANE and the HAX1 genes have been observed in those patients. This study was conducted to genetically screen six Iranian families with SCN who have at least one affected person. In the first step, all exons and intron boundaries of ELANE and HAX1 genes were sequenced in probands. Cases with no pathogenic mutations were tested through whole-exome sequencing (WES). Analysis showed five different variants in ELANE (c.377 C>T), HAX1 (c.130_131 insA), HYOU1 (c.69 G>C and c.2744 G>A) and SHOC2 (c.4 A>G) genes in four families. We found that two out of six families had mutations in ELANE and HAX1 genes. Moreover, we found two novel mutations at the HYOU1 gene that had not previously been reported, as well as a pathogenic mutation at SHOC2 with multiple phenotypes, that will contribute to determining the genetic basis for SCN. Our study revealed that WES could help diagnose SCN, improve the classification of neutropenia, and rule out other immunodeficiencies such as autoimmune neutropenia, primary immunodeficiency diseases, and inherited bone marrow failure syndromes.

Case Report of a Novel NFkB Mutation in a Lymphoproliferative Disorder Patient.

BACKGROUND: Lymphoproliferative disorders include a heterogeneous list of conditions that commonly involve dysregulation of lymphocyte proliferation resulting in lymphadenopathy and bone marrow infiltration. These disorders have various presentations, most notably autoimmune manifestations, organomegaly, lymphadenopathy, dysgammaglobulinemia, and increased risk of chronic infections. CASE PRESENTATION: A young boy presented with symptoms overlapping different lymphoproliferative disorders, including episodes of chronic respiratory tract infections, dysgammaglobulinemia, lymphadenopathy-associated with splenomegaly as well as skin rashes. Genetic studies revealed multiple heterozygous variants, including a novel mutation in the NFκB1 gene. CONCLUSION: This novel mutation can reveal new aspects in the pathogenesis of lymphoproliferative disorders and propose new treatments for them.

A 3-Year-Old Boy with an Xp21 Deletion Syndrome: A Case Report.

BACKGROUND: Chromosome Xp21 deletion syndrome is a rare X-linked recessive defect that occurs as a result of multiple gene deletions, including Glycerol kinase (GK) and its neighboring genes, dystrophin, which causes Duchenne muscular dystrophy (DMD), and NR0B1, which causes congenital adrenal hypoplasia (CAHhttps://www.omim.org/entry/300200). Patients usually present with glycerol kinase deficiency, congenital adrenal hypoplasia, Duchenne muscular dystrophy, hyperglycerolemia, and glyceroluria, associated with DMD and/or CAH, growth failure, myopathy, osteoporosis, mental retardation, and psychomotor retardation. CASE PRESENTATION: Herein, we report a 3-year- old boy from Iraq who had bloody diarrhea, food intolerance and abdominal cramp, adrenal insufficiency, recurrent fevers, tuberculosis (TB) infection, cervical abscess, oral thrush, cervical and mediastinal lymphadenopathies, developmental delay, and undescended testis. His parents are non-consanguine and had no family history of diseases. Next generation sequencing demonstrated a hemizygote deletion in chromosome X. CONCLUSION: Loss of a large part of the X-chromosome most likely can explain the clinical findings of this patient. Contiguous gene deletion syndrome in Xp21 should be considered after diagnosing adrenal insufficiency to treat metabolic complications efficiently.

MicroRNAs and Diabetes Mellitus Type 1.

Type 1 diabetes mellitus is a multifactorial, progressive, autoimmune disease with a strong genetic feature that can affect multiple organs, including the kidney, eyes, and nerves. Early detection of type 1 diabetes can help critically to avoid serious damages to these organs. MicroRNAs are small RNA molecules that act in post-transcriptional gene regulation by attaching to the complementary sequence in the 3'-untranslated region of their target genes. Alterations in the expression of microRNA coding genes are extensively reported in several diseases, such as type 1 diabetes. Presenting non-invasive biomarkers for early detection of type 1 diabetes by quantifying microRNAs gene expression level can be a significant step in biotechnology and medicine. This review discusses the area of microRNAs dysregulation in type 1 diabetes and affected molecular mechanisms involved in pancreatic islet cell formation and dysregulation in the expression of inflammatory elements as well as pro-inflammatory cytokines.

Novel Variants of DOCK8 Deficiency in a Case Series of Iranian Patients.

BACKGROUND: Dedicator of Cytokinesis 8 (DOCK8) deficiency, the most frequent cause of autosomal recessive hyper immunoglobulin (Ig)E syndrome, is a rare combined immunodeficiency. OBJECTIVE: In this study, we report seven patients, with consanguineous parents, with five novel variants within the DOCK8 gene. METHODS: For genetic analysis, we performed Whole Exome Sequencing (WES) or targeted sequencing by means of Next-generation sequencing (NGS) for some of the patients. For others, Sanger sequencing, Fluorescence-activated cell sorting (FACS), or polymerase chain reaction (PCR) were used. RESULTS: We report five novel variants within the DOCK8 gene: three deletions (deletion of exons 4-12, 24-30, and 22-27), one frameshift (LRG_196:g.189315dup;p.(Leu1052Profs*7)), and a splice region variant (LRG_196t1:c.741+5G>T). Patients presented with skin lesions, food allergy, candidiasis, otitis, recurrent respiratory infections, short stature, aortic aneurism, gynecomastia, and coarse facial features. Patients had leukocytosis, eosinophilia, lymphopenia, and monocytosis, elevated IgE, IgG, IgA, reduced IgM and IgA levels. Patients had a low percentage of CD3+ and CD4+ cells and a high percentage of CD19+, CD27+CD19+, and recent thymic emigrants T cells. The percentage of natural killer cells was increased in one of the patients while it was decreased in another patient. One patient died due to disseminated intravascular coagulation after hematopoietic stem cell transplantation. CONCLUSION: We reported novel variants within the DOCK8 gene and highlighted the risk of aneurysms in these patients, which have been rarely reported in these patients.

Targeting Hypertension Screening in Low- and Middle-Income Countries: A Cross-Sectional Analysis of 1.2 Million Adults in 56 Countries.

Background As screening programs in low- and middle-income countries (LMICs) often do not have the resources to screen the entire population, there is frequently a need to target such efforts to easily identifiable priority groups. This study aimed to determine (1) how hypertension prevalence in LMICs varies by age, sex, body mass index, and smoking status, and (2) the ability of different combinations of these variables to accurately predict hypertension. Methods and Results We analyzed individual-level, nationally representative data from 1 170 629 participants in 56 LMICs, of whom 220 636 (18.8%) had hypertension. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or reporting to be taking blood pressure-lowering medication. The shape of the positive association of hypertension with age and body mass index varied across world regions. We used logistic regression and random forest models to compute the area under the receiver operating characteristic curve in each country for different combinations of age, body mass index, sex, and smoking status. The area under the receiver operating characteristic curve for the model with all 4 predictors ranged from 0.64 to 0.85 between countries, with a country-level mean of 0.76 across LMICs globally. The mean absolute increase in the area under the receiver operating characteristic curve from the model including only age to the model including all 4 predictors was 0.05. Conclusions Adding body mass index, sex, and smoking status to age led to only a minor increase in the ability to distinguish between adults with and without hypertension compared with using age alone. Hypertension screening programs in LMICs could use age as the primary variable to target their efforts.

A novel homozygous RAG1 mutation is associated with severe combined immunodeficiency and neurological presentations

Introduction and objectives: Severe combined immunodeficiency (SCID) is a subset of primary immunodeficiency diseases caused by a hereditary deficiency of the adaptive immune system. Mutation in recombination activating gene (RAG) is known as the underlying genetic cause of SCID. RAG protein plays a pivotal role in V(D)J recombination which is the main process to assemble lymphocyte antigen receptors during T- and B-cell development. The patients are characterized by recurrent infections, failure to thrive, chronic diarrhea, and fever, in early infancy. Herein, we present a case of SCID with rare neurological manifestations affected by a mutation in RAG1. Patients and methods: The patient was a 15-month-old infant born to a consanguineous family. She was presented with neurological abnormalities including facial nerve palsy, seizure, and decreased consciousness. Next-generation sequencing (NGS)-based primary immunodeficiency disease (PID)-gene panel screen and Sanger sequencing were performed to identify the genetic mutation. Results: We found a novel homozygous missense mutation in RAG1, c.1210C>T,p.Arg404Trp, which was predicted to be deleterious (combined annotation dependent depletion, CADD score of 27.4). Both parents were heterozygous carriers for this mutation. According to her laboratory data, both T cell and B cell numbers were decreased and the patient was diagnosed as RAG1- SCID. Conclusions: SCID is a pediatric emergency with a variety of manifestations in infants. Therefore, accurate diagnosis importantly in the case of rare manifestations must be considered in these patients. Our findings point toward the importance of genetic assessment for early diagnosis and timely treatment of this disorder (AU)

Novel G6PC3 Mutations in Patients with Congenital Neutropenia: Case Reports and Review of the Literature.

BACKGROUND: Severe congenital neutropenia (SCN4) caused by mutations in glucose-6- phosphatase catalytic subunit 3 (G6PC3) is characterized by recurrent infections due to severe neutropenia, may be accompanied by other extra-hematopoietic manifestations; including structural heart defects, urogenital abnormalities, prominent superficial venous markings, growth retention, and inflammatory bowel diseases with rare incidence. The homozygous or compound heterozygous mutations of G6PC3 are responsible for most cases of autosomal recessive SCN4. Herein, we present two cases of SCN4 affected by novel mutations in the G6PC3, in addition to a summarized list of variants in G6PC3 gene that are reported as pathogenic and related to the SCN4 phenotype. CASE PRESENTATION: Herein, we present two cases of SCN4; the first case was a three-months old boy with severe neutropenia and prior history of hospitalization due to umbilical separation, umbilical herniation, omphalitis, and pyelonephritis; and the second case was an eight-year-old with a history of neutropenia, recurrent and severe episodes of intractable diarrhea, refractory rectovaginal and rectoperineal fistula, congenital inguinal hernia, and ASD type 2. Whole exome sequencing was performed for both cases, which revealed two novel homozygous missense mutations in G6PC3 that were predicted to be deleterious; c.337G>A, p. Gly113Arg in the first case and c.479C>T; P. Ser160Leu in the second case. To our knowledge, both of these two mutations have not been reported in the G6PDC3 gene. CONCLUSION: In patients with severe neutropenia with varying extra hematopoietic syndrome, mutation of G6PC3 should be suspected after ruling out other mutations related to neutropenia. This study pointed toward novel G6PC3 mutations that should be considered in order to diagnose patients with severe congenital neutropenia.

Introduction on Coronavirus Disease (COVID-19) Pandemic: The Global Challenge.

By driving the ongoing pandemic of coronavirus disease 2019 (COVID-19), coronaviruses have become a significant change in twenty-first-century medicine, healthcare systems, education, and the global economy. This chapter rapidly reviews the origin, immunopathogenesis, epidemiology, diagnosis, clinical manifestations, and potential therapeutics of COVID-19. It would also explore the effects of the introduction of a single virus, the so-called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), on the public health preparedness planning.

Novel BTK mutation in X-linked agammaglobulinemia: Report of a 17-year-old male

Introduction and objectives: X-linked agammaglobulinemia (XLA), the first known primary immunodeficiency, is caused by rare mutations in Bruton’s tyrosine kinase (BTK) gene. Mutations in the BTK gene lead to a failure in the development and maturation of B-cell linage. A decreased number of B-cells results in agammaglobulinemia and increased susceptibility to a variety of infections. Therefore, patients with XLA usually manifest with repetitive bacterial infections, such as upper respiratory tract infections, septic arthritis, osteomyelitis, and urinary tract infections, since their infancy. Patients We report a 17-year-old Iranian boy with XLA, referred to us with a history of severe and recurrent episodes of bacterial infections for a period of six years. Results Genetic analysis using the whole Exome sequencing revealed a hemizygous missense mutation in the BTK gene (c.428 A > T, p.His143Leu). Conclusion To our knowledge, c.428 A > T has not been reported in the BTK gene (AU)

Novel BTK mutation in X-linked agammaglobulinemia: Report of a 17-year-old male.

INTRODUCTION AND OBJECTIVES: X-linked agammaglobulinemia (XLA), the first known primary immunodeficiency, is caused by rare mutations in Bruton's tyrosine kinase (BTK) gene. Mutations in the BTK gene lead to a failure in the development and maturation of B-cell linage. A decreased number of B-cells results in agammaglobulinemia and increased susceptibility to a variety of infections. Therefore, patients with XLA usually manifest with repetitive bacterial infections, such as upper respiratory tract infections, septic arthritis, osteomyelitis, and urinary tract infections, since their infancy. PATIENTS: We report a 17-year-old Iranian boy with XLA, referred to us with a history of severe and recurrent episodes of bacterial infections for a period of six years. RESULTS: Genetic analysis using the whole Exome sequencing revealed a hemizygous missense mutation in the BTK gene (c.428 A > T, p.His143Leu). CONCLUSION: To our knowledge, c.428 A > T has not been reported in the BTK gene.

Clinical and Mutation Description of the First Iranian Cohort of Infantile Inflammatory Bowel Disease: The Iranian Primary Immunodeficiency Registry (IPIDR).

We describe a cohort of 25 Iranian patients with infantile inflammatory bowel disease (IBD), 14 (56%) of whom had monogenic defects. After proper screening, patients were referred for whole exome sequencing (WES). Four patients had missense mutations in the IL10 RA, and one had a large deletion in the IL10 RB. Four patients had mutations in genes implicated in host:microbiome homeostasis, including TTC7A deficiency, and two patients with novel mutations in the TTC37 and NOX1. We found a novel homozygous mutation in the SRP54 in a deceased patient and the heterozygous variant in his sibling with a milder phenotype. Three patients had combined immunodeficiency: one with ZAP-70 deficiency (T+B+NK-), and two with atypical SCID due to mutations in RAG1 and LIG4. One patient had a G6PC3 mutation without neutropenia. Eleven of the 14 patients with monogenic defects were results of consanguinity and only 4 of them were alive to this date.

microRNA-related single-nucleotide polymorphisms and breast cancer.

Breast cancer, as the most common cancer in women which affects patients both mentally and physically, requires great attention in many areas and many levels as this cancer is known to be multifactorial. Single-stranded molecules called microRNAs with near 22 nucleotides are seen to act in central dogma of molecular biology by inhibiting the translation process; it is demonstrated that any alteration in their sequence especially single-nucleotide polymorphisms (SNPs) may lead into increasing the breast cancer risk. miR-SNPs are considered to be the potential biomarkers for early detection of breast cancer. As a result, this review documents the well-known miR-SNPs that are known to be associated with breast cancer. In this regard, two principals were discussed: (a) SNPs in the target genes of microRNAs and the alteration in gene expression due to this phenomenon; (b) changes based on the SNPs in the microRNA coding region and the impact on their interaction with target messenger RNA.