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الملخص: أهداف البحث: عيوب القلب الوعائية وراثية بشكل كبير وحوالي ثلث عيوب القلب الخلقية ناتجة عن عيوب القلب الوعائية. باستخدام التحليل اللاحق لعيوب القلب المخروطية -بيانات دراسة الترابط الجينومي الكامل ذات الصلة، تم افتراض مسار جديد مفترض لنقل الإشارات، يسمى ''فارس2-بك3كا-أ ك ت''، المرتبط بعيوب القلب الوعائية. كنا نهدف بشكل أساسي إلى التحقق من مسار ''فارس2-بك3كا-أ ك ت” بشكل تجريبي باستخدام المقياسين ''فارس2” و ''بيب3” في كل من مرضى عيوب القلب والعينة الضابطة، وإنشاء مثبط ''بيب3''، كواحد من مسببات عيوب القلب الضارة ذات الصلة، باستخدام استراتيجية تصميم الأدوية القائمة على ''أ ك ت''. طرق البحث: تم إجراء التنميط الجيني ''ار اس 2517582” والتعبير النسبي لـ ''فارس2” في 207 أفراد باستخدام تفاعل البلمرة المتسلسل الكمي، إلى جانب ذلك تم أيضا قياس ''بيب3” المحررة فى البلازما لدى 190 فردا باستخدام تقنية المقايسة الامتصاصية المناعية للإنزيم المرتبط. استخدمنا نموذج ميزات ''أ ك ت''-حامل الخاصة الدوائية لاكتشاف خصم ''بيب3” باستخدام أدوات حسابية متعددة وأدوات تقدير شبيهة بالعقاقير. النتائج: تم تأكيد إمراض عيوب القلب الوعائية بسبب فرط التحفيز المفرط لـ ''فارس2-بك3كا-أ ك ت” عن طريق ''فارس2” المرتفع و ''بيب3” في مرضى عيوب القلب الوعائية. حددنا جزيئا صغيرا جديدا، يسمى ''بيسب322''، قادرا على أن يقاوم ارتباط ''بيب3''، وتم منحه الأولوية من خلال الفحص الافتراضي لـ 21 جزيئا صغيرا افتراضيا. أظهر ''بيسب322” الحد الأدنى من التغير النسبى لاختلاف موقع جزيئاته ''رمسد''، وتقارب ربط عال، وثابت تفكك أقل من مجمع بيب3-أ ك ت” بمقدار 1.99 كيلو كالوري/مول مما يؤدي إلى تحول التوازن التفضيلى نحو تكوين معقد ''بيسب322-أ ك ت''. عرضت ''بيسب322” الخصائص الدوائية المقبولة وخصائص تشابه الأدوية وفقا لقاعدة ليبنيسكي و قاعدة امتصاص وتوزيع وتمثيل الغذاء وإفرازه المكونة من خمسة مصنفات. هذا هو أول جزيء محتمل كشبيه علاجى الدواء لمرضى عيوب القلب الوعائية الذين يعانون من ارتفاع ''بيب3''. الاستنتاجات: ''بيب3” هي مؤشرات حيوية تشخيصية مفيدة لمرضى عيوب القلب. يعد نموذج ميزات ''أ ك ت''-حامل الخاصة الدوائية نهجا ممكنا لاكتشاف المزيد من مضادات تأثير''بيب3''. يوصى بإجراء المزيد من اختبارات التطوير لجزئ ''بيسب322''. Abstract: Objectives: Conotruncal heart defects (CTDs) are highly heritable, and approximately one-third of all congenital heart defects are due to CTDs. Through post-analysis of GWAS data relevant to CTDs, a new putative signal transduction pathway, called Vars2-Pic3ca-Akt, associated with CTD has been hypothesized. Here, we aimed to validate the Vars2-Pic3ca-Akt pathway experimentally by measuring Vars2 and PIP3 in patients with CTDs and controls, and to construct a PIP3 inhibitor, as one of harmful-relevant CTD pathogenesis, through an Akt-based drug design strategy. Methods: rs2517582 genotype and relative Vars2 expression in 207 individuals were determined by DNA sequencing and qPCR respectively, and free plasma PIP3 in 190 individuals was quantified through ELISA. An Akt-pharmacophore feature model was used to discover PIP3 antagonists with multiple computational and drug-like estimation tools. Results: CTD pathogenesis due to Vars2-Pic3ca-Akt overstimulation was confirmed by elevated Vars2 and PIP3 in patients with CTDs. We identified a new small molecule, 322PESB, that antagonizes PIP3 binding. This molecule was prioritized via virtual screening of 21 hypothetical small molecules and it showed minimal RMSD change, high binding affinity andlower dissociation constant than PIP3-Akt complex by 1.99 Kcal/Mol, thus resulting in an equilibrium shift toward 322PESB-Akt complex formation. Moreover, 322PESB exhibited acceptable pharmacokinetics and drug likeness features according to ADME and Lipinski's rule of five classifiers. This compound is the first potential drug-like molecule reported for patients with CTDs with elevated PIP3. Conclusion: PIP3 is a useful diagnostic biomarker for patients with CTDs. The Akt-pharmacophore feature model is a feasible approach for discovery of PIP3 signalling antagonists. Further 322PESB development and testing are recommended.

Abstract Background Stratification analysis studies showed that ethnicity has a significant association regarding MTHFR C677T variant and congenital heart diseases (CHDs) risk, and many published studies have controversial conclusions toward this association. Methods In this study, the association between the MTHFR C677T variant and the risk for CHDs was evaluated in 91 children with CHD and 95 healthy controls, as new cases, by using restriction fragment length polymorphism (RFLP) technique. Besides that, 2 case–control studies in the Egyptian population published before 2021 were included in this meta-analysis. The association was assessed by the odds ratio (OR) with a 95% confidence interval (CI) based on 294 alleles in CHD cases and 286 alleles in controls. Results The overall meta-analysis showed a significant association between MTHFR C677T variant and CHDs risk in Egyptian children with heterogeneity (Heterogeneity = 0.001) in all the genetic models with the highly significant association in T versus C allele (pooled OR 1.89, 95% CI 1.31–2.74; p value

Abstract Background Childhood dilated cardiomyopathy (CDCM) is the most common cardiomyopathy in children and it is risk factor to heart failure and sudden death. Most of the different etiologic factors which have been postulated to DCM are idiopathic, and its pathogenesis remains uncertain. So it was worth investigating the potential DCM pathogenicity models to establish early noninvasive diagnosis parameters especially in CDCM patients. Beside that miRNAs in the circulatory blood are genetically considered the best option for noninvasive diagnosis; also, implementation of miRNAs as early diagnostic markers for children with DCM is urgent because those children have high risk to sudden heart death. We aimed to identify discriminator diagnostic circulatory miRNA expression levels in CDCM patients. Results The expression levels of miR-454-3p and miR-194-5p were found significant upregulated (p value = 0.001 and 0.018; CI 95%, respectively), while miR-875-3p was found significant downregulated (p value = 0.040; CI 95%). A receiver operating characteristic (ROC) curve analysis showed significant AUC = 1.000 and 0.798 for miR-454-3p and miR-194-5p, respectively, and the optimal discriminated diagnostic cut-points were computed by index of union (IU) method. Enrichment analysis for the potential targeted mature mRNAs by miR-454-3p and miR-194-5p pointed that Ca, Na and K ions homeostasis in cardiac sarcolemma consider potential CDCM pathogenicity model. Conclusions miR-454-3p and miR-194-5p are highly influencing noninvasive biomarkers for CDCM, and further circulatory miRNAs-implicated studies are highly recommended.

Abstract Background Interstitial lung disease (ILD) is a broad heterogeneous group of lung disorders that is characterized by inflammation of the lungs. Surfactant dysfunction disorders are a rare form of ILD diseases that result from mutations in surfactant protein C gene (SFTPC) with prevalence of approximately 1/1.7 million births. SFTPC patients are presented with clinical manifestations of ILD ranging from fatal respiratory failure of newborn to chronic respiratory problems in children. In the current study, we aimed to investigate the spectrum of SFTPC genetic variants as well as the correlation of the SFTPC gene mutations with ILD disease in twenty unrelated Egyptian children with diffuse lung disease and suspected surfactant dysfunction using Sanger sequencing. Results Sequencing of SFTPC gene revealed five variants: c.42+35G>A (IVS1+35G>A) (rs8192340) and c.43-21T>C (IVS1-21T>C) (rs13248346) in intron 1, c.436-8C>G (IVS4-8C>G) (rs2070687) in intron 4, c.413C>A p.T138N (rs4715) in exon 4, and c.557G>Ap.S186N (rs1124) in exon 5. Conclusion The present study confirms the association of detecting variants of SFTPC with surfactant dysfunction disorders.

Abstract Background Wolf–Hirschhorn syndrome (WHS) (OMIM 194190) is a multiple congenital anomalies/intellectual disability syndrome. It is caused by partial loss of genetic material from the distal portion of the short arm of chromosome. Methods We studied the phenotype–genotype correlation. Results We present the clinical manifestations and cytogenetic results of 10 unrelated Egyptian patients with 4p deletions. Karyotyping, FISH and MLPA was performed for screening for microdeletion syndromes. Array CGH was done for two patients. All patients exhibited the cardinal clinical manifestation of WHS. FISH proved deletion of the specific WHS locus in all patients. MLPA detected microdeletion of the specific locus in two patients with normal karyotypes, while array CGH, performed for two patients, has delineated the extent of the deleted segments and the involved genes. LETM1, the main candidate gene for the seizure phenotype, was found deleted in the two patients tested by array CGH; nevertheless, one of them did not manifest seizures. The study emphasized the previous. Conclusion WHS is a contiguous gene syndrome resulting from hemizygosity of the terminal 2 Mb of 4p16.3 region. The Branchial fistula, detected in one of our patients is a new finding that, to our knowledge, was not reported.

Introduction: There is a growing evidence of immune system alteration in children with Autism Spectrum Disorder (ASD). These changes may include higher levels of pro-inflammatory cytokines in plasma, Cerebrospinal Fluid (CSF) and brain cells. Aim: To evaluate the imbalance of the immune system in autism through correlating some immunological markers (C3, C4, CD4, IL12 and IL17) with severity of ASD. Materials and Methods: The current case-control study included 120 subjects, 60 autistic children and 60 healthy control obtained from the Clinical Genetics Clinic, National Research Centre, Egypt from the period between December 2014 to December 2016. All candidates were subjected to full clinical evaluation in addition to ElectroEncephaloGraphy (EEG), hearing test and estimation of interleukins (IL12- IL17), C3-C4, CD4 levels in blood samples. Independent t-test, Chi-square test or McNemar test were used to analyse the data. Results: The levels of IL12 (27.47 ±7.15) and IL17 (1630.46±310.42) were significantly higher, (p= 0.026, 0.005) respectively, while levels of CD4 were significantly lower (37.93±3.25), (p