Year 2021, Volume 4 - Issue 1

Background: C-terminal tensin-like (CTEN) is a protein located at focal adhesions and has been reported to be an oncogene in the colon, breast, lung, and gastric cancer. In this study, we investigated whether two other proposed mechanisms, i.e., epidermal growth factor receptor (EGFR) and Signal transducer and activator of transcription 3 (STAT3) signaling were involved in regulating CTEN expression. Methodology: Initially, we manipulated EGFR signaling by (i) stimulation with epidermal growth factor (EGF) and (ii) inhibition by the PD153035 in the colorectal cancer cell lines SW620 and C32. In C32, EGF stimulation resulted in the upregulation of KRAS and CTEN, whereas exposure to PD153035 resulted in the downregulation of both KRAS and CTEN. EGFR activation and inhibition were reflected by, respectively, increased and decreased cell motility although the effect of EGFR activation was lost by CTEN knockdown. In SW620, which harbors a KRAS mutation, modulating EGFR activity in this way did not affect either KRAS or CTEN. STAT3 signaling has also been reported to positively regulate CTEN. We tested this in SW620 by directly knocking down STAT3 and exposing cells to interleukin-6 (an activator of STAT3). STAT3 knockdown resulted in increased CTEN, whereas STAT3 activation resulted in the downregulation of CTEN. Results: Testing for KRAS expression showed that STAT3 was negatively regulating KRAS, and this was reflected in the CTEN expression. Functional analysis, however, showed that the inhibition of STAT3 resulted in a reduction of cell motility in a K RAS and CTEN-independent manner. Conclusion: We conclude that both EGFR signals through KRAS to modulate CTEN (and consequently integrin- linked kinase/focal adhesion kinase) and stimulates cell motility. STAT3, however, negatively regulates KRAS and consequently CTEN although its net effect is to stimulate motility through an alternative mechanism.

Background: Systemic lupus erythematosus (SLE) is a complex trait characterized by the production of a range of autoantibodies and a diverse set of clinical phenotypes, including skin rash, neuropsychiatric and musculoskeletal symptoms, and lupus nephritis (LN). Mannan-binding lectin (MBL) is a recognition molecule of the lectin pathway of complement activation. We investigated MBL gene polymorphism at exon 1 codon 54 as a potential biomarker for SLE nephritis in the current study. Methodology: A case–control study screened 70 participants. They were included in the study from the outpatient clinic or the inpatient section of the Rheumatology Department at Sohag University Hospital during July 2017-June 2019 for MBL gene polymorphism at exon 1 codon 54, which was detected by polymerase chain reaction using sequence-specific priming. Result: There was a predominance of AA (wild) genotype in the control group (40%). Patient groups had a statistically significant equal higher frequency of heterozygous polymorphism (AB) (76%) than the controls. BB genotype showed a statistically significant lowest frequency in the LN group (p-value = 0.04). Conclusions: MBL AB genotyping was more frequent in SLE patients either with or without nephritis than in the normal Egyptian population. BB genotyping was less frequent in LN patients than in patients without nephritis. The present study supports that the carriage of MBL AB genotype (heterozygous polymorphism at codon 54) was associated with both SLE and LN development in normal Egyptians.

Background: Primary prevention of primary congenital glaucoma (PCG) includes improving families of children with PGC. We evaluated the level of knowledge and attitudes of parents of children on PCG in Saudi Arabia. Methodology: This was a personal interview-based survey of parents of children with PCG at a tertiary eye hospital in Saudi Arabia. The study was conducted in 2018. A close-ended questionnaire in Arabic was used. Demographic data were collected on the children and parents. Clinical data on PCG were collected from electronic case records. Five questions each on knowledge and attitudes toward genetic counseling were queried. A Likert-type scale was used to collect the responses. Rasch analysis was carried out for knowledge and attitudes. The score was correlated with demographics and clinical determinants. p < 0.05 was considered statistically significant. Results: The study sample comprised 60 participants. The median Rasch score for knowledge on genetic counseling for PCG was -4.57 [interquartile range (IQR) -7.28; -1.0]. The median Rasch score for attitudes toward genetic counseling for PCG was -8.9 (IQR -11.6: -5.9). Parents with more than one family member with PCG had a significantly higher knowledge than those with one family member with PCG (p = 0.007). Knowledge of etiology and genetic counseling was significantly better if the child had residual vision amenable to low vision care (p < 0.001). The Rasch scores for knowledge and attitude were positively correlated (p < 0.001). Conclusion: Knowledge of the cause of PCG and genetic counseling was high among parents. The positive attitude toward genetic counseling could be useful for the primary prevention of CG in Saudi Arabia.

Background: There is a high rate of consanguinity and related genetic diseases in the general population of Saudi Arabia. Studies have been conducted to address the level of awareness about consanguineous marriages (CM); however, targeted young female studies are still limited. The association between consanguinity and socio-demographic information and the prevalence of consanguinity among educated female university students of Princess Nourah Bint Abdulrahman University (PNU), Riyadh, Saudi Arabia, is being addressed in the present study. Methodology: A cross-sectional web-based questionnaire study was conducted randomly among PNU students from October 3 to November 2, 2019. Multivariable data analysis was conducted, and an odds ratio was calculated to identify factors associated with CM and health outcomes. Results: Among the 637 students who completed the questionnaire, consanguinity was significantly higher among participants than their parents, as 37.88% of the 293 married participants had CM. A strong correlation was found between parents and their daughters; consanguinity was highest (52.27%) in the daughters of parents who were in consanguineous marriages themselves. The general high level (91.51%) of awareness about CM’s consequences and their link to genetic diseases was found. However, a lack of knowledge about the type of diseases was noted among participants. Diabetes and blood diseases were the most common diseases in different CM groups. Conclusion: Despite the high levels of awareness, more targeted awareness campaigns are needed, especially among the younger generation.

Background: According to American Cancer Society, an estimated 268,600 new cases of invasive breast cancer was diagnosed among women, and nearly 50,000 women were under age 50 years. Therefore, the identification of young age breast cancer patients can have a collosal impact on treatment, and medical follow-up. The present study aimed to understand the young age breast cancer pathophysiology and redound new BRCA variants to literature. Methodology: This was a double-centre study performed in the Medical Genetics Department of Kahramanmaras Necip Fazıl City Hospital. In this study, sixty female patients, who are under 45 years old, diagnosed with primer breast cancer in the oncology clinic of the same hospital and Kahramanmaraş Sutcu İmam University were included. The patients were selected for BRCA mutation testing based on NCCN Guideline Version 3.2019 BRCA1/2 Testing Criteria. Relatives who meet the same criteria from the same family were not included to prevent repetition. Patients with known other cancer syndromes were also excluded. Results: We found that Luminal-B type breast cancer was the most frequent subtype (p < 0.001), patients with Luminal-A subtype breast cancer had significantly smaller tumor size and smaller grade than those had other subtypes of breast cancer at diagnosis stage (p = 0.03 and p < 0.001, respectively). Regarding tumor localization, the breast carcinomas were mostly localized in the right breast (53.3%). Two patients (3.3%) had BRCA1 pathogenic mutation and five patients (8.3%) had BRCA2 pathogenic mutation. Additionally, we found two new variations in BRCA2 gene (c.478_488delGTATGTGGGAG and c.8830 A>T (rs4987047). All BRCA1/2 MLPA results were normal. Conclusion: The incidence of young age breast cancer varies among countries, and it is higher in developing countries. Understanding of young age breast cancer cases will be helpful to provide suitable treatment options and will help to reduce the death rate of these patients.

In vitro fertilization (IVF) is a process by which an egg is extracted by needle aspiration and then combined with a sperm so that fertilization can occur outside the body. Genetic defects, such as chromosomal abnormalities, are considered rare among the general population; however, even though their incidence among IVF-conceived children is uncommon, several alarming studies were published on the increased risk of chromosomal abnormalities IVF/intracytoplasmic sperm injection (ICSI)-conceived children compared to universal rates. This study aimed to review the literature and present data to answer whether IVF or ICSI is associated with an increased risk of chromosomal abnormalities inborn after IVF/ICSI treatment compared to spontaneously conceived children. Relevant published scientific articles were searched in the Medline database, using combinations of the following key terms: "IVF", "in vitro fertilization", "ICSI", "intracytoplasmic sperm injection", "natural conception", "spontaneous conception" along with "chromosomal abnormalities", "chromosomal defects", "sex chromosome aneuploidy", and "trisomy". The eligible studies were considered as studies exploring the association of IVF/ICSI with chromosomal abnormalities compared to spontaneous conception. The search included studies published from 1992 to 2018. The results for the association of chromosomal abnormalities and IVF remain unclear. As many studies proved a significant increase in chromosomal abnormalities and syndromes among the IVF population, other studies were contradicting and contributed the abnormalities to several environmental and technical factors.

Background: Sphingosine Phosphate Lyase Insufficiency Syndrome SPLIS is a recently described condition, which is associated with loss of function mutations in SGPL1, encoding sphingosine-1-phosphate lyase. In 2017, several groups reported this novel childhood syndrome that featured a wide range of presentations including fetal hydrops, steroid-resistant nephrotic syndrome (SRNS), primary adrenal insufficiency (PAI), rapid or insidious neurological deterioration, immunodeficiency, acanthosis and endocrine abnormalities. Case Presentation: A 7-year-old boy was presented to us with primary adrenal insufficiency on hydrocortisone following pediatrics endocrinology at our hospital. Genetic testing identified a homozygous variant of sphingosine-1-phosphate lyase 1 (NM 003901: exon8: c.665G>A: p.R222Q). At the same time, he was found to have nephrotic syndrome, and renal function rapidly deteriorated. Biopsy of the right kidney showed focal segmental glomerulosclerosis with collapsing features and acute interstitial nephritis. Later, he received a living- related renal transplant. He is doing well after the transplant. Conclusion: Patients with primary adrenal insufficiency should be carefully followed to develop nephrotic syndrome features, and molecular testing is the key to the diagnosis of the underlying etiology. This is the first reported case with sphingosine-1-phosphate lyase 1 that underwent renal transplantation in our region.

Background: Ethylmalonic encephalopathy (EE) is a devastating early-onset inborn error of metabolism, and heterogenous disorders manifest as chronic diarrhea, petechial rash, and neurological manifestations. The mutation in the ETHE1 gene leads to hydrogen sulfide accumulation and eventually results in mucosal cell damage in the large intestines and vascular endothelial cells system. Case presentation: Here, we describe four patients from three different tribes in Oman, and the clinical data revealed that the four patients shared an early-onset phenotype and the neurological manifestations were variable. The biochemical markers, specifically the urine organic acid and hyperlactimic acidosis, supported and tailored the diagnosis. Molecular diagnosis was confirmed by full gene sequencing of the ETHE1 gene in the index case and followed by target variant testing for others. Interestingly, all four patients identified to harbor the same homozygous missense pathogenic variant (c.487c > t) in the ETHE1 gene, and their parents were all heterozygous. These findings indicate that we probably have a founder variant associated with EE in our area. Conclusion: These findings are of great importance for diagnosis and surveillance for Omani families with EE. Given the relatively high number and frequency of genetic diseases in the region and the limited resources, screening for these founder mutations should provide a rapid and cost-effective tool for molecular diagnosis. Additionally, these findings should help in designing appropriate measures for carrier screening measures at the regional level.

Background: Congenital myasthenic syndromes (CMSs) are a clinically and genetically heterogeneous group of disorders caused by mutations that lead to altered neuromuscular junction transmissions. Recently, the solute carrier family 25 member 1 (SLC25A1) gene was described to cause CMS type 23. This gene encodes a mitochondrial citrate carrier, associated mainly with a severe neurometabolic disease like combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). Case presentation: Here, we report four Emirati patients with a homozygous missense variant in SLC25A1 with a phenotype restricted to relatively mild CMS. We performed whole-exome sequencing (WES) in two relatives who presented with CMS to identify the underlying causative gene. Conclusion: The WES analysis revealed the presence of a homozygous c.205G>T (p.Asp69Tyr) [(c.226G>T (p.Asp76Tyr)] in the SLC25A1 gene; the same variant was identified in the other members in this family with the same phenotype. This suggests that c.205G>T (p.Asp69Tyr) [(c.226G>T p.(Asp76Tyr)] is associated with a relatively mild CMS phenotype and can be considered as a founder mutation in our region.

Background: Depending on the genetic mutation, mitochondrial hepatopathy has a variable presentation. Spontaneous recovery is a rare occurrence in these patients. However, complete recovery is possible in infants having t-RNA5-methylaminomethyl-2-thiouridylate methyl-transferase (TRMU) gene mutation. Case presentation: A 53-day-old female child presented with hepatopathy and lactic acidosis. Genetic work up showed she has a mitochondrial respiratory chain disorder due to the TRMU gene mutation. Very few patients with isolated hepatic involvement have been described in the literature. We are reporting the first case from India of transient hepatopathy due to heterozygous TRMU gene mutation. Recovery was spontaneous at 4 months of age. Conclusion: Complete recovery is possible in infants having TRMU mutation if they are supported through and survive the acute phase. The identification of TRMU mutation could impact clinical management.