Molecular and Genetic Medicine

Massively parallel sequencing or next generation sequencing (NGS) panel-based testing has paved the way for rapid clinical molecular diagnosis of diseases by sequencing all known involved genes. One such condition is retinitis pigmentosa (RP), which is a genetically heterogeneous disorder that can be caused by autosomal recessive, autosomal dominant, digenic, or X-linked pathogenic variants, making a genetic diagnosis challenging. Large deletions and duplications in the RP genes have been known to contribute to a significant proportion of cases, and therefore, deletion/duplication analysis by various methods are often to be added to the RP NGS panel testing. In this report, we describe the process of identifying a large novel deletion in the X-linked RP2 gene that presented novel challenges for the NGS-based molecular testing.

Polycystic ovarian syndrome (PCOS) is an endocrine disorder that affects women at reproductive age. This syndrome gives rise to various consequences, from reproductive, dermatological, nervous and psychiatric problems to different features of metabolic syndrome. Due to the complexity of PCOS, candidate gene approaches are insufficient to understand its molecular mechanism. A systems biology approach that requires strong integration of experimental and computational biology to understand the complex biological systems could be used in examining multiple interacting genes and their products that lead to PCOS. This short communication discusses the available omics studies that have been conducted in PCOS.

Combined SCC and SqCC of salivary gland are defined as a composite tumor and it represents an even more rare entity, often recognized just after evaluation of the surgical specimen. Here we report an extraordinary case of combined SCC and SqCC of the parotid gland in a 73-year-old man with a prior medical history of cutaneous squamous cell carcinoma. A computed tomography scan showed a 3 cm-sized heterogeneous mass in the parotid region while no other primary tumor or metastasis and lymphadenopathy were detected. The patient underwent to a partial parotidectomy and morphological and immunohistochemical features of the tumor were consisting in combined SCC and SqCC. SqCC component was immunoreactive for p40 whereas SCC neoplastic cells resulted strongly positive either for synaptophysin and chromogranin and negative either for p40 or high molecular weight cytokeratins. To identify the main putative genetic alterations specific for each histotype component, we performed a molecular profiling of FGFR1, MET, MYC, TP53, BRAF, NOTCH1, EGFR, NFE2L2, PDGFRa, cKIT, and PIK3CA genes. Interestingly, these analyses did not disclose any known genetic alterations in any neoplastic component of the combined tumor. To the best of our knowledge, this is the first detailed report of a combined small cell and squamous cell carcinoma of the parotid gland. Our case did not show any known molecular signature. Further investigation will clarify the pathogenesis and relationship of the individual components and will be of great utility for the treatment of these extremely rare entity..

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) system is one of the promising methods for targeted genome editing without interfering with intracellular mechanisms. This system is useful for treatment of various diseases and identification of genes responsible for those diseases. In the current study, we performed scientometric analysis along with text-mining of PubMed reports on CRISPR based research in medicine. The upshot of the study revealed cancer, tumour and inherited hereditary diseases as the most prominently studied diseases using the CRISPR tool. Here, we present the outcome of the analysis in the form of a brief systematic review on application of CRISPR tools in the field of medical research using network analysis emphasizing the mostly studied diseases. The review will definitely help the researchers working in the field of medical research to get an overall idea as well as shape their objectives.

Symbiotic relationship between microbial flora in human body and our body plays a key role in maintaining a healthy life. It has been suggested that microbiota of our body protects us against pathogens, supports our immune system and plays a role in the synthesis of certain necessary micronutrients. Human microbiota is composed of bacteria, fungi and viruses, and their number exceeds 10 trillion in total. This number is 100 times more than the number of other cells in our body. The human gastrointestinal system and the genitourinary system have been showed to have several types of microbes that could have symbiotic functions in several systems including the reproductive system of the females. There have been several developments recently that enabled the researchers to determine the microbial diversity and rates in our body in a surprising accuracy with next-generation sequencing technique (NGS). Such developments have been the turning point in the understanding of relationship between microbiota and human health.

Membrane traffic has been widely studied in recent decades, and now it is clear that its participation in biological processes such as cellular migration, mitosis, and immune response, among others, is crucial and determinant. During the development of the nervous system, membrane trafficking organizes both the differential distribution and degradation of specific components, among others. Failures in these functions lead to the development of neurological pathologies that can be progressive, chronic or even lethal such as Alzheimer's, Huntington's and Parkinson's diseases. These pathologies have significant health and economic costs in many countries. For this reason, research is being focused on the study of those components (mainly proteins) involved in membrane traffic during health and disease. In this short communication, we summarize main findings and state of the art discussion about the functions of some membrane trafficking components during development, as well as the implications of their dysfunction into the progression of neurological pathologies.

Brugada Syndrome (BrS) is an inherited channelopathy, with an autosomal dominant transmission, incomplete penetrance and variable expressivity, associated with high risk of malignant arrhythmias and sudden cardiac death, predominantly in young men. Even though nearly 30 years of study about this syndrome has gone past, several key points still remain to elucidate: The lack of a definite consensus regarding the management of asymptomatic patients, the influence of drug challenging test, the role of genetic test, symptoms and electrophysiological study in the decision-making process, the management of apparently low risk patients, the role of epicardial ablation are only some of the topics of ongoing controversy. This case report highlights these important and still debated topics about BrS, suggesting how much is still unknown about it.

With the development of surgical techniques and implementation of adjuvant chemotherapy, the outcomes for patients with locally advanced colon cancer are improved. The necessity of neoadjuvant treatment has led to increasing interest. This Mini review summarizes the progress in neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy.

Restless leg syndrome occurs frequently among patients with end-stage renal disease. Although the etiopathogenesis of restless leg syndrome has not been fully elucidated, advanced age, female gender, positive family history, chronic renal failure, pregnancy and folic acid and iron deficiency have all been implicated. Recent studies found a diminished ability of D2 receptors to bind ligands and reduced 18F-dopa uptake in the putamen and striatum in patients with restless leg syndrome. A marked increase in the plasma concentrations of glycation end-products was observed in uremic patients. Methylglyoxal is a major end-product of glycolysis. Methylglyoxal is a reactive carbonyl species that is formed during glucose metabolism. Methylglyoxal may increase the dopamine concentration and other toxic metabolites such as salsolinol in dopaminergic neurons and dopamine-mediated oxidative stress could contribute to damage of dopaminergic neurons.

Oncophagy (cancer–autophagy interplay) became a focus of interest after awarding Yoshinori Ohsumi the Nobel Prize for Physiology or Medicine for his work elucidating the mechanism of autophagy. One of the interesting hot spots in the research work is the growing evidence of the fundamental role of autophagy in cancer. Autophagy is degradation process, intimately intertwined with cellular metabolism, stress, genetic instability and cellular death. Autophagy modulation could be a therapeutic rational for emerging cancer. We aim by this mini-review to precise the role of autophagy in carcinogenesis whether it is with or against.

This case report describes the diagnosis of a familial juvenile nephronophthisis in a 17-year-old boy and emphasises on the increasing importance of genetic testing in patients with chronic kidney disease. A 17-yearold Iraqi refugee presented with abdominal pain and was incidentally found to have renal impairment (creatinine 279 μmol/L, urea 12.6 mmol/L, calculated eGFR for age 28 ml/min/1.73 m²). Urinalysis showed no proteinuria nor haematuria and renal ultrasound and computed tomography revealed small kidneys (left=8.4 cm and right=7.9 cm). The patient's brother had end-stage renal disease and commenced on peritoneal dialysis at the age of 19 with a presumed diagnosis of cystic renal hypodysplasia. Genetic testing revealed homozygous deletion of 2q13 that encompasses NPHP1 giving a diagnosis of juvenile nephronophthisis. Nephronophthisis is an autosomal recessive disorder characterised by normal to small cystic kidneys and an insidious onset of end-stage renal disease. It is the most common genetic renal disease in the first two decades of life and mortality is related to the complications of renal failure. It is caused by mutations in the NPHP genes, which encode proteins involved in the function of primary cilia, centrosomes and basal bodies. Nephronophthisis may be isolated or part of a syndrome and diagnosis is established by genetic testing.

Sleep remains one of the supreme mysteries in science. In the history few years, great advances have been made to healthier realize this happening. Human genetics has contributed appreciably to this faction, as many features of sleep have been found to be inborn. Discoveries about these genetic variations that affect human sleep will assist us in understanding the underlying mechanism of sleep. Here we recapitulate latest discoveries about the genetic variations affecting the timing and duration of sleep, EEG patterns. To wrap up, Author also discusses some of the sleep-related neurological disorders such as Autism Spectrum Disorder and Alzheimer’s disease. The potential challenges and future directions of human genetics in sleep research.

Purpose: Owing to persistent controversy regarding the use of routine antibiotic prophylaxis in patients undergoing transarterial chemoembolization (TCAE) and the availability of several new studies published on the subject, we conducted an up-to-date meta-analysis to provide the best current evidence. The aim of the article is to assess whether antibiotic prophylaxis is effective in reducing the incidence of infectious complications after TCAE.

Materials and methods: PubMed, Google scholar, Cochrane Central Register of Controlled Trials, CNKI and Wan-Fang database were searched through October 2018 for randomized or non-randomized controlled trials for comparing the use of prophylactic antibiotics in TACE with placebo or no antibiotics were included in the review. Pooled effect estimates were calculated using fixed-effects and random-effects models.

Results: Eight studies with a total number of 1672 of procedures were included in the meta-analysis. We found no evidence of publication bias or heterogeneity among the studies. Antibiotic prophylaxis did not reduce the incidence of infectious complications (risk ratio [RR] 0.88, 95% confidence interval [CI] 0.62 to 1.24, p=0.464) and the rate of patients developing fever (RR 1.04, 95% CI 0.91 to 1.19, p=0.595). When the analyses were stratified into subgroups, there was no evidence that study design substantially influenced the estimate of effects. Furthermore, the sensitivity analysis confirmed the stability of our results.

Conclusion: Although current evidence demonstrates that the routine use of antibiotic prophylaxis for TACE may not be necessary, more evidence from advanced multi-center studies is needed to provide instruction for the use of prophylactic antibiotics.

Background: Tigecycline (TGC) is a last resort antibiotic having broad spectrum antibacterial activity against gram-negative bacteria. Beyond its standard dosing regimen, a double dosing regimen has been practicing for last couple of years to achieve adequate drug concentration in the targeted body tissues. TGC interferes with the mitochondrial protein translation process and may lead to non-anion gap acute metabolic acidosis (NAGAMA) with low blood-pH level. The main objective of this retrospective study was to evaluate the frequency of high dose TGCinduced NAGAMA events in the South Asian critically ill patients.

Methods: The retrospective data of 24 critically ill patients of an intensive care unit (ICU) were considered for this study. Patients of this study received high dose of TGC. Including all necessary laboratory data, patients’ anion gap, blood-pH level data in pre and post-TGC therapy were also recorded from the ICU’s clinical-record archive. All the data were analyzed to find out the significance of NAGAMA event with high dose TGC therapy.

Results: Among the patients administered with high dose TGC, 45.83% (11; n=24) of patients were experienced with NAGAMA event and in every 2.18 patients, 1 patient developed this event. Among those 11 patients, 63.64% of patients were recovered within 24 hours after stopping the TGC therapy and the rest of the patients (36.36%) were recovered within 48 hours, where 4 patients required therapeutic intervention to overcome the NAGAMA event.

Conclusion: High dose TGC-induced NAGAMA event is an unusual event, globally. Mitochondrial toxicity is a TGC-associated adverse event and the related NAGAMA is a detrimental clinical consequence. However, the complete mechanism of this event is even not fully clear but, caution should be taken in the use of high dose TGC mostly in the critically ill patients.

Ischemic heart disease is the most common cause of death in both female and male genders. Though coronary artery disease is the most common determinant of ischemia in males, women present more often chest pain associated with normal epicardial coronary arteries. In females, coronary microvascular dysfunction plays a key role in developing symptoms and imbalance between delivery and request of coronary blood flow. Coronary ion channels play a major role in the regulation of coronary blood flow. According to the epidemiological, pathophysiological and clinical differences between male and female genders in ischemic heart diseases, it is legitimate to suspect the possible impact of gender on modulating the effect of cardiovascular risk factors. Whereas it is well known the role of estrogens in cardiovascular system, the role of genetics it has never been extensively addressed. Considering the high prevalence of coronary microvascular dysfunction in females and the regulatory function of coronary ion channels, we speculate that genetic differences in genes encoding the ion channels could be a major determinant of the difference in ischemic phenotypic expression among genders. Our previous study clearly shows that the single nucleotide polymorphism rs5215_GG of KCNJ11 gene encoding for coronary KATP channel is more prevalent in women and reduces the susceptibility to ischemic heart disease regardless the presence of other cardiovascular risk factors. This finding suggests a major role of genetics in the development of ischemic heart diseases and warrants further studies to evaluate the usefulness of genetic screening in clinical daily practice.

Major arrhythmias and sudden cardiac death in young and apparently healthy people are usually the first manifestation of cardiac channelopathies (CC). CC include long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. Identification and proper management of these diseases is a challenge for the clinical cardiologists, which could benefit from collaboration with geneticists and other physicians due to relevant genetic, molecular, biologic and psychologic implications. Medical awareness of these issues is growing fast as clinical research provides continue update. In this paper, we provide a comprehensive review of CC. The genes associated with CC and their relative role are here illustrated and summarized

Neural crest is a remarkable transient cell population present during embryogenesis, with the ability to differentiate into a multitude of cell types. Depending on anterior to posterior position, neural crest derivatives (cranial, vagal, trunk and sacral, respectively) migrate and commit to restricted lineages. Neuroblastoma is a tumor of infancy and locates along sympathetic ganglia. Based on tumor location and tumor cell gene expression, neuroblastoma is believed to arise from cells of the trunk neural crest-derived sympathetic nervous system. Here we establish the gene expression pattern of trunk enriched- as well as neuroblastoma associated genes over time during early embryogenesis. We show that genes associated with trunk neural crest development as well as neuroblastoma progression are highly expressed at time points when trunk neural crest cells delaminate from the neural tube, undergo epithelial-to-mesenchymal transition and migrate throughout the embryonic body. Using recently established crestosphere cultures – in vitro maintenance of multipotent and self-renewing neural crest stem cells – we confirm that diagnostic and prognostic markers of neuroblastoma are highly enriched in trunk- as compared to cranial neural crest. Our data strengthen a trunk neural crest origin for neuroblastoma

The Brugada syndrome is an autosomal dominant rare form of cardiac arrhythmia and has been associated with high risk of sudden cardiac death predominantly in younger male patients. It is associated with polymorphic ventricular arrhythmia/ventricular fibrillation, Supraventricular arrhythmia mainly atrial fibrillations and Wolf- Parkinson white syndrome. Patients can be presented with symptom like syncope, palpitation, sudden cardiac death and asymptomatically. Several pathogenic genes have been identified as associated with the disease but SCN5A is the most prevalent one. Several genetic mutations of different subunits of sodium, calcium and potassium channel have been involved. The management of Brugada syndrome and Wolf-Parkinson-White syndrome in patients with atrial fibrillation should be generally includes implantable cardioverter defibrillator and Radiofrequency catheter ablations. This brief review focuses on recent clinical diagnosis, genetic basis and advances in pharmacological treatment of Brugada syndromes with atrial fibrillation and wolf-Parkinson white syndrome.

A 60-year-old man was diagnosed with gastric cancer by endoscopy in our cancer center. Preoperative CT scan showed thickening of the cardia and enlarged lymph nodes in hepatogastric space. Consequently, he accepted total gastrectomy and Roux-en-Y reconstruction. Immunohistochemical detection showed intense positivity for GST-n and Pgp antibodies and negativity for EGFR, ERCC1, P53, Ki67 and HER-2. Surprisingly, within one month, the patient had multiple asymptomatic cutaneous nodules in the left neck, right subclavian, left armpit, left upper abdomen, lower abdomen, right groin and lumbodorsal region. Abdominal CT scan showed a 22 × 22 mm highdensity lesion in the splenorenal space, as well as cutaneous nodules in the left upper abdomen, lower abdomen and right groin. Histopathologic examination of cutaneous biopsy showed a poorly differentiated signet-ring cell carcinoma consistent with a diagnosis of secondary metastasis of primary gastric carcinoma. The patient received “DOF” chemotherapy which do benefit to halt the disease progression. He decided not to continue with chemotherapy and died of multiorgan metastasis 2 months later.

Hermansky-Pudlak syndrome (HPS) is a rare inherited multisystem disorder characterized by oculocutaneous albinism and diathesis, and in some patients with pulmonary fibrosis. It is caused by defective biogenesis and trafficking of lysosome-related organelles. Genetically HPS is heterogeneous, and ten loci have been identified as causative genes. The majority of these genes encode subunits of multi-protein complexes named biogenesis of lysosomes-related organelles complex. Mutations within HPS1 and HPS4 genes lead to pulmonary fibrosis in HPS type1 and type 4 patients respectively and are the leading cause of mortality. A 14 years Senegalese boy who was initially diagnosed with oculocutaneous albinism was recruited with his father after informed consent for genetic analysis. In his clinical history, there was no bleeding tendency or clinical episodes of hemorrhagic diathesis. One of his sisters had albinism and died from lung complications at the age of 15 years. The patient was referred to the pneumology department of Fann Hospital in Dakar for further explorations. The high-resolution computed tomography (HRCT) scans of the lungs revealed no evidence of diffuse interstitial lung disease, pleuropericardial effusion, bronchiectasis, pulmonary hypertension, intra pulmonary/mediastinal mass or lymphadenopathy. Mutation screening by Albinism NGS panel identified a homozygous mutation located in exon 6 of the HPS1 gene, c.421C˃T (p.Gln141*), in the Proband while his father showed heterozygosity for this mutation. The parents of the proband are not consanguineous and this may suggest a common allele of HPS1 among Senegalese people. Patients with oculocutaneous albinism should therefore be evaluated for Hermansky-Pudlak syndrome by mutational screening within the ten HPS genes.