Expanding the clinical and immunological phenotypes of PAX1-deficient SCID and CID patients.

Paired box 1 (PAX1) deficiency has been reported in a small number of patients diagnosed with otofaciocervical syndrome type 2 (OFCS2). We described six new patients who demonstrated variable clinical penetrance. Reduced transcriptional activity of pathogenic variants confirmed partial or complete PAX1 deficiency. Thymic aplasia and hypoplasia were associated with impaired T cell immunity. Corrective treatment was required in 4/6 patients. Hematopoietic stem cell transplantation resulted in poor immune reconstitution with absent naïve T cells, contrasting with the superior recovery of T cell immunity after thymus transplantation. Normal ex vivo differentiation of PAX1-deficient CD34+ cells into mature T cells demonstrated the absence of a hematopoietic cell-intrinsic defect. New overlapping features with DiGeorge syndrome included primary hypoparathyroidism (n = 5) and congenital heart defects (n = 2), in line with PAX1 expression during early embryogenesis. Our results highlight new features of PAX1 deficiency, which are relevant to improving early diagnosis and identifying patients requiring corrective treatment.

Combination treatment of bortezomib and epirubicin increases the expression of TNFRSF10 A/B, and induces TRAIL-mediated cell death in colorectal cancer cells.

Colorectal cancer is one of the most common cancers worldwide, affecting the colon and rectum. A major problem in the treatment of colorectal cancer is acquired chemoresistance, including resistance against death receptor-induced apoptosis. Therefore, investigating new biomarkers for the treatment of the disease and sensitization strategies against TRAIL might be of high clinical importance. TNFRSF10A/B are known as death receptors for TRAIL-induced apoptotic cell death. In this study, we used multiple bioinformatic tools and experimental analyses to investigate the role of TRAIL receptors TNFRSF10A and TNFRSF10B in colorectal cancer. We also identified the potential effect of bortezomib and epirubicin in the induction of TRAIL-mediated apoptotic cell death. Here, we showed that TNFRSF10 A/B expressions are upregulated in various tumor types, including COAD, and its high expression is decreased with the different clinicopathological parameters in COAD. We also found an association between TNFRSF10 A/B expression and tumor molecular subtypes. We further detected the association between the expression of TNFRSF10 A/B and immune cell tumor infiltration, including B cells, CD8+ T cells, neutrophils and dendritic cells. In addition, we showed that combining bortezomib and epirubicin treatment leads to the upregulation of TNFRSF10 A/B in colorectal cancer cells in vitro. The increase in the expression of death receptors was correlated with higher active caspase-3 levels following the incubation of cells with recombinant TRAIL protein, which is a ligand for TNFRSF10 A/B receptors. Our results suggest that TNFRSF10 A/B may be a marker to differentiate tumor molecular subtypes in colorectal cancer. The expression of TNFRSF10 A/B may be associated with the recruitment of immune cells into tumors and the development of tumor suppression. The combination of bortezomib and epirubicin treatment might sensitize colorectal cancer cells to TRAIL-induced apoptosis via the upregulation of death receptor.

A novel INPP4A mutation with pontocerebellar hypoplasia, myoclonic epilepsy, microcephaly, and severe developmental delay.

BACKGROUND: The inositol polyphosphate 4-phosphatase intracellular signaling pathway is susceptible to genetic or epigenetic alterations that may result in major neurological illnesses with clinically significant pons and cerebellum involvement. CASE REPORTS: A seven-year-old girl with pontocerebellar hypoplasia, resistant myoclonic epilepsy with axial hypotonia, microcephaly, atypical facial appearance, nystagmus, ophthalmoplegia, hyperactive tendon reflexes, spasticity, clonus, extensor plantar response, contractures in wrists and ankles and growth retardation, whole-exome sequencing was performed and a homozygous "NM_001134225.2:c.646C > T, p.(Arg216Ter)" variant was found in the INPP4A gene. CONCLUSION: INPP4A mutations should be kept in mind in cases with severely delayed psychomotor development, progressive microcephaly, resistant myoclonic epilepsy, isolated cerebellum, and pons involvement.

Investigation of sub-chromosomal changes in males with idiopathic azoospermia by chromosomal microarray analysis.

Azoospermia consists of a significant proportion of infertility aetiology in males. Although known genetic abnormalities may explain roughly the third of infertility cases, the exact aetiology is still unclear. Chromosomal microarrays are widely used to detect sub chromosomal abnormalities (e.g., microdeletions and microduplications). This study aimed to investigate aetiology in patients with idiopathic azoospermia by using the chromosomal microarray method to detect possible sub chromosomal changes. Twenty-eight patients (with a mean age of 30.4 ± 9 years) that had been diagnosed with idiopathic azoospermia between January 2019 and December 2020 were included in the study. Genomic DNA isolated from the blood of patients were amplified using polymerase chain reaction and was subjected to chromosomal microarray analysis. A total of six microdeletions were identified as clinically significant: one pathogenic copy number variation (CNV), four likely pathogenic CNVs, and one CNV of unknown clinical significance. However, clinical findings indicated that these microdeletions, with variable expression levels, may affect the spermatogenesis process and induce azoospermia. Future investigations regarding the functional effect of these deletions may contribute to our understanding of azoospermia aetiology.

Maternal Germline Mosaicism of a de Novo TUBB2B Mutation Leads to Complex Cortical Dysplasia in Two Siblings.

Introduction: Complex cortical dysplasia with other brain malformations-7 (a.k.a. polymicrogyria) caused by mutations in TUBB2B gene is a clinically heterogeneous condition. Case report: We report two siblings with polymicrogyria. Brain MRI showed polymicrogyria, small brainstem, thin corpus callosum and fused basal ganglia. Karyotypes and chromosomal microarray analysis were normal. By whole exome sequencing, there were a de novo variant of c.728C > T (p.P243L) in both siblings and a common single nucleotide polymorphism (SNP) (c.718C > T) in both siblings and the mother. Seminal DNA analysis obtained from father was normal. Conclusion: Maternal germline mosaicism was considered because the sequencing result of the father's sperm was normal, two siblings had the same disease, and both patients and mother had the same SNP.

IL-17A, MCP-1, CCR-2, and ABCA1 polymorphisms in children with non-alcoholic fatty liver disease / Polimorfismos IL-17A, MCP-1, CCR-2 e ABCA1 em crianças com doença hepática gordurosa não alcoólica

Abstract Objective: The prevalence of non-alcoholic fatty liver disease in children has risen significantly, owing to the worldwide childhood obesity epidemic in the last two decades. Non-alcoholic fatty liver disease is closely linked to sedentary lifestyle, increased body mass index, and visceral adiposity. In addition, individual genetic variations also have a role in the development and progression of non-alcoholic fatty liver disease. The aim of this study was to investigate the gene polymorphisms of MCP-1 (-2518 A/G) (rs1024611), CCR-2 (190 G/A) (rs1799864), ABCA1 (883 G/A) (rs4149313), and IL-17A (-197 G/A) (rs2275913) in obese Turkish children with non-alcoholic fatty liver disease. Methods: The study recruited 186 obese children aged 10 -17 years, including 101 children with non-alcoholic fatty liver disease and 85 children without non-alcoholic fatty liver disease. Anthropometric measurements, insulin resistance, a liver panel, a lipid profile, liver ultrasound examination, and genotyping of the four variants were performed. Results: No difference was found between the groups in respect to age and gender, body mass index, waist/hip ratio, or body fat ratio. In addition to the elevated ALT levels, AST and GGT levels were found significantly higher in the non-alcoholic fatty liver disease group compared to the non non-alcoholic fatty liver disease group (p < 0.05). The A-allele of IL-17A (-197 G/A) (rs2275913) was associated with non-alcoholic fatty liver disease (odds ratio [OR] 2.05, 95% confidence interval: 1.12 -3.77, p = 0.02). Conclusions: The findings of this study suggest that there may be an association between IL-17A (-197 G/A) (rs2275913) polymorphism and non-alcoholic fatty liver disease development in obese Turkish children.

Resumo Objetivo: A prevalência de doença hepática gordurosa não alcoólica em crianças aumentou significativamente devido à epidemia de obesidade infantil em todo o mundo nas últimas duas décadas. A doença hepática gordurosa não alcoólica está intimamente ligada ao estilo de vida sedentário, ao aumento do índice de massa corporal e à adiposidade visceral. Além disso, variações genéticas individuais também têm um papel no desenvolvimento e na progressão da doença hepática gordurosa não alcoólica. O objetivo deste estudo foi investigar os polimorfismos genéticos MCP-1 (-2518 A/G) (rs1024611), CCR-2 (190 G/A) (rs1799864), ABCA1 (883 G/A) (rs4149313) e IL-17A (-197 G/A) (rs2275913) em crianças turcas obesas com doença hepática gordurosa não alcoólica. Métodos: O estudo recrutou 186 crianças obesas entre 10 e 17 anos, inclusive 101 crianças com doença hepática gordurosa não alcoólica e 85 crianças sem doença hepática gordurosa não alcoólica. Medidas antropométricas, resistência à insulina, painel hepático, perfil lipídico, exame ultrassonográfico do fígado e genotipagem de quatro variantes foram feitos. Resultados: Nenhuma diferença foi encontrada entre os grupos em relação à idade e sexo, índice de massa corporal, relação cintura/quadril ou proporção de gordura corporal. Além dos níveis elevados de ALT, os níveis de AST e GGT foram significativamente maiores no grupo doença hepática gordurosa não alcoólica em comparação com o grupo não doença hepática gordurosa não alcoólica (p < 0,05). O alelo A de IL-17A (-197 G/A) (rs2275913) foi associado à doença hepática gordurosa não alcoólica (odds ratio [OR] 2,05, intervalo de confiança de 95%: 1,12-3,77, p = 0,02). Conclusões: Os achados deste estudo sugerem que pode haver uma associação entre o polimorfismo IL-17A (-197 G/A) (rs2275913) e o desenvolvimento da doença hepática gordurosa não alcoólica em crianças turcas obesas.

IL-17A, MCP-1, CCR-2, and ABCA1 polymorphisms in children with non-alcoholic fatty liver disease.

OBJECTIVE: The prevalence of non-alcoholic fatty liver disease in children has risen significantly, owing to the worldwide childhood obesity epidemic in the last two decades. Non-alcoholic fatty liver disease is closely linked to sedentary lifestyle, increased body mass index, and visceral adiposity. In addition, individual genetic variations also have a role in the development and progression of non-alcoholic fatty liver disease. The aim of this study was to investigate the gene polymorphisms of MCP-1 (-2518 A/G) (rs1024611), CCR-2 (190 G/A) (rs1799864), ABCA1 (883 G/A) (rs4149313), and IL-17A (-197 G/A) (rs2275913) in obese Turkish children with non-alcoholic fatty liver disease. METHODS: The study recruited 186 obese children aged 10-17 years, including 101 children with non-alcoholic fatty liver disease and 85 children without non-alcoholic fatty liver disease. Anthropometric measurements, insulin resistance, a liver panel, a lipid profile, liver ultrasound examination, and genotyping of the four variants were performed. RESULTS: No difference was found between the groups in respect to age and gender, body mass index, waist/hip ratio, or body fat ratio. In addition to the elevated ALT levels, AST and GGT levels were found significantly higher in the non-alcoholic fatty liver disease group compared to the non non-alcoholic fatty liver disease group (p<0.05). The A-allele of IL-17A (-197 G/A) (rs2275913) was associated with non-alcoholic fatty liver disease (odds ratio [OR] 2.05, 95% confidence interval: 1.12-3.77, p=0.02). CONCLUSIONS: The findings of this study suggest that there may be an association between IL-17A (-197 G/A) (rs2275913) polymorphism and non-alcoholic fatty liver disease development in obese Turkish children.

Importance and usage of chromosomal microarray analysis in diagnosing intellectual disability, global developmental delay, and autism; and discovering new loci for these disorders.

BACKGROUND: Chromosomal microarray analysis is a first-stage test that is used for the diagnosis of intellectual disability and global developmental delay. Chromosomal microarray analysis can detect well-known microdeletion syndromes. It also contributes to the identification of genes that are responsible for the phenotypes in the new copy number variations. RESULTS: Chromosomal microarray analysis was conducted on 124 patients with intellectual disability and global developmental delay. Multiplex ligation-dependent probe amplification was used for the confirmation of chromosome 22q11.2 deletion/duplication. 26 pathogenic and likely pathogenic copy number variations were detected in 23 patients (18.55%) in a group of 124 Turkish patients with intellectual disability and global developmental delay. Chromosomal microarray analysis revealed pathogenic de novo Copy number variations, such as a novel 2.9-Mb de novo deletion at 18q22 region with intellectual disability and autism spectrum disorder, and a 22q11.2 region homozygote duplication with new clinical features. CONCLUSION: Our data expand the spectrum of 22q11.2 region mutations, reveal new loci responsible from autism spectrum disorder and provide new insights into the genotype-phenotype correlations of intellectual disability and global developmental delay.

Prevalence of known mutations in the MEFV gene in a population screening with high rate of carriers.

The Familial Mediterranean Fever (FMF) shows an autosomal recessive pattern of inheritance and affects certain ethnic groups. Disease is caused by mutations in MEFV gene and more than 180 mutations have been defined in affected individuals. Current study aimed to determine the frequency-type of the mutations for MEFV gene in Sivas-middle Anatolian city. The cohort was composed of 3340 patients. MEFV gene mutations were studied by multiplex PCR based reverse hybridization stripAssay method. Patients' clinical features were; family history: 68%, erysipelas-like erythema: 17.6%, fever: 89.9%, abdominal pain: 84.2%, peritonitis: 90.2%, arthritis: 33%, pleuritis: 14.2%, parental consanguinity: 21.2%. Current results revealed that M694V is the most frequent mutation (43.12%), followed by E148Q (20.18), M680I(G/C) (15.00%) and V726A (11.32%). The study population has a high rate of carriers and the E148Q mutation frequency was found to be highest when compared to the other regions of Turkey and other Mediterranean groups.