B-cells absence in patients diagnosed as inborn errors of immunity: a registry-based study.

Hypogammaglobulinemia without B-cells is a subgroup of inborn errors of immunity (IEI) which is characterized by a significant decline in all serum immunoglobulin isotypes, coupled with a pronounced reduction or absence of B-cells. Approximately 80 to 90% of individuals exhibit genetic variations in Bruton's agammaglobulinemia tyrosine kinase (BTK), whereas a minority of cases, around 5-10%, are autosomal recessive agammaglobulinemia (ARA). Very few cases are grouped into distinct subcategories. We evaluated phenotypically and genetically 27 patients from 13 distinct families with hypogammaglobinemia and no B-cells. Genetic analysis was performed via whole-exome and Sanger sequencing. The most prevalent genetic cause was mutations in BTK. Three novel mutations in the BTK gene include c.115 T > C (p. Tyr39His), c.685-686insTTAC (p.Asn229llefs5), and c.163delT (p.Ser55GlnfsTer2). Our three ARA patients include a novel homozygous stop-gain mutation in the immunoglobulin heavy constant Mu chain (IGHM) gene, a novel frameshift mutation of the B-cell antigen receptor complex-associated protein (CD79A) gene, a novel bi-allelic stop-gain mutation in the transcription factor 3 (TCF3) gene. Three patients with agammaglobulinemia have an autosomal dominant inheritance pattern, which includes a missense variant in PIK3CD, a novel missense variant in PIK3R1 and a homozygous silent mutation in the phosphoinositide-3-kinase regulatory subunit (RASGRP1) gene. This study broadens the genetic spectrum of hypogammaglobulinemia without B-cells and presented a few novel variants within the Iranian community, which may also have implications in other Middle Eastern populations. Notably, disease control was better in the second affected family member in families with multiple cases.

New molecular insights into the A218V variant impact on the steroidogenic acute regulatory protein (STAR) associated with 46, XY disorders of sexual development.

Disorders of sexual development (DSD) are an abnormal congenital conditions associated with atypical development of the urogenital tract and external genital structures. The steroidogenic acute regulatory (STAR) gene, associated with congenital lipoid adrenal hyperplasia (CLAH), is included in the targeted gene panel for the DSD diagnosis. Therefore, the genetic alterations of the STAR gene and their molecular effect were examined in the CLAH patients affected with DSD. Ten different Iranian families including twelve male pseudo-hermaphroditism patients with CLAH phenotype were studied using genetic linkage screening and STAR gene sequencing in the linked families to the STAR locus. Furthermore, the structural, dynamical, and functional impacts of the variants on the STAR in silico were analyzed. Sanger sequencing showed the pathogenic variant p.A218V in STAR gene, as the first report in Iranian population. Moreover, modeling and simulation analysis were performed using tools such as radius of gyration, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and molecular docking showed that p.A218V variant affects the residues interaction in cholesterol-binding site and the proper folding of STAR through increasing H-bound and the amount of α-Helix, deceasing total flexibility and changing fluctuations in some residues, resulting in reduced steroidogenic activity of the STAR protein. The study characterized the structural and functional changes of STAR caused by pathogenic variant p.A218V. It leads to limited cholesterol-binding activity of STAR, ultimately leading to the CLAH disease. Molecular dynamics simulation of STAR variants could help explain different clinical manifestations of CLAH disease.

Alpha-lipoic acid improves sperm motility in infertile men after varicocelectomy: a triple-blind randomized controlled trial.

RESEARCH QUESTION: Does supplementation with alpha-lipoic acid (ALA) enhance sperm parameters and/or the status of sperm lipid peroxidation and DNA fragmentation in men who have undergone microsurgical repair of a varicocele? DESIGN: Individuals with a varicocele who had undergone varicocelectomy were divided into two groups receiving either 600 mg of ALA or an identical placebo for 80 days. Semen samples obtained from the participants before surgery and after completion of the course of medication were analysed and compared. Participants, clinicians and data analysts were blinded to the randomization sequence. RESULTS: In the ALA group, total motility (P = 0.01) and progressive motility (P = 0.002) of the spermatozoa were significantly higher compared with the placebo group after surgery. Sperm lipid peroxidation and DNA damage (assessed by sperm chromatin structure assay) showed significant decreases in both the ALA and placebo groups (P ≤ 0.02) after treatment. CONCLUSIONS: An 80-day course of ALA medication after surgical repair improves total motility and progressive motility of the spermatozoa in individuals with a varicocele.

Ciliary and immune dysfunctions and their genetic background in patients with non-cystic fibrosis bronchiectasis in Central Iran.

OBJECTIVE: Bronchiectasis is usually caused by recurrent bacterial infections and is characterized by irreversible dilation of the bronchi. In this study, we aimed to give an overview of the genetic backgrounds of patients with non-cystic fibrosis bronchiectasis (NCFB) that have been suspected to an underlying ciliary dysfunction or inborn error of immunity (IEI). METHOD: This is a retrospective cross-sectional study. Seventy-one NCFB patients who were referred to the Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran, from 1996 to 2020 were included. These patients were referred to this center for immunological and genetic evaluation. Genetic analysis with whole-exome sequencing and Sanger sequencing was confirmed in 30 patients. However, the genetic evaluations of 41 patients were either still under evaluation or the patients had refused to be genetically evaluated. RESULT: Thirty-eight of our 71 patients (53.52%) were diagnosed with ciliary dysfunction and the detected mutations included mutations in the CCDC65, DNAH11, RSPH1, CCDC40, and GAS8 genes as well as a novel mutation. Thirty-three patients (46.47%) had an IEI and the detected mutations included mutations of the following genes: TNFRSF13B, PTPN2, ZNF341 BTK, TCF3, CD79a, PIK3CD, JAGN1, WAS, RFXANK, STK4, GSDMD, and NEMO. CONCLUSION: This study presents an overview of the underlying ciliary and immune dysfunctions and their genetic mutations in NCFB in a highly consanguine population. This would give us a better understanding of the etiologies and the known and novel genetic mutations in NCFB in Iran and, in turn, in the Middle East and North Africa (MENA) region.

Characterization of a novel androgen receptor gene variant identified in an Iranian family with complete androgen insensitivity syndrome (CAIS): a molecular dynamics simulation study.

Androgen insensitivity syndrome (AIS) is a common form of 46, XY disorder in sex development disease (DSD). It is due to the androgen receptor (AR) gene mutations and includes clinical subgroups of complete AIS (CAIS) and partial AIS (PAIS), along with a vast area of clinical heterogeneity of completely normal female external genitalia to male infertility. In this study, the Whole Exome Sequencing (WES) was utilized to detect the cause of DSD in a consanguineous Iranian family with two female patients with normal external genitalia and 46, XY karyotype. Sanger sequencing was applied to validate the candidate variant. Next, we predicted the structural alteration induced by the variant on AR protein using bioinformatics analysis such as molecular dynamic (MD) and molecular docking simulations. WES results identified a novel hemizygous p.L763V variant in the AR gene in the proband that was compatible with the X-linked recessive pattern of inheritance. Bioinformatics studies confirmed the loss of AR function. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, it was categorized as pathogenic. This study broadens the AR mutation spectrum and introduces the novel p.L763V missense pathogenic variant leading to AR failure to bind to its ligand, and the resulting CAIS clinical subgroup. This study presents a prosperous application of WES and bioinformatics analysis to recognize the underlying cause of DSD in Iran, necessary for its clinical/psychological management.Communicated by Ramaswamy H. Sarma.

A Novel Homozygous Pathogenic Variant in CYP11B1 in a Female Iranian Patient with 11B Hydroxylase Deficiency.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) addresses a number of autosomal recessive disorders characterized by the enzyme defects in steroid hormones biosynthesis. The second common form of CAH is caused by mutations in the CYP11B1 gene. Here, we reveal a novel mutation in the CYP11B1 gene related to the 11ßOHD phenotype. METHODS AND RESULTS: Sequence analysis of the CYP11B1 gene in a 19-year-old Iranian woman with the 11ßOHD phenotype was performed. In silico analysis and molecular docking were done. A novel missense homozygous variant c.1351C > T (p.L451F) in the CYP11B1 gene was identified in the patient and, according to American College of Medical Genetics and Genomics criteria, was categorized as likely pathogenic. Protein docking showed destructive effects of the variant on the CYP11B1 protein-ligand interactions. CONCLUSION: This study broadens the CYP11B1 mutation spectrum and introduces the novel p.L451F likely pathogenic variant leading to destructive effects on protein-ligand interactions. Our results provide reliable information for genetic counseling and molecular diagnostics of CAH.