Antifibrotic effect of the P2X7 receptor antagonist A740003 against acute myocardial infarction-induced fibrotic remodelling.

Post-acute myocardial infarction (AMI) fibrosis is a pathophysiologic process characterised by activation of the profibrotic mediator, transforming growth factor-ß (TGF-ß). AMI is associated with a substantial increase in the levels of extracellular adenosine triphosphate (eATP), which acts on the purinergic P2X7-receptor (P2X7-R) and triggers an inflammatory response that contributes to myocardial fibrotic remodelling. P2X7-R has been implicated in several cardiovascular diseases; however, its role in the regulation of cardiac fibrosis remains unclear. Therefore, the current study aimed to determine the effect of the P2X7-R antagonist, A740003, on post-AMI fibrosis, via the profibrotic TGF-ß1/Smad signalling pathway, and elucidate whether its effect is mediated via the modulation of GSK-3ß. AMI was induced by surgical ligation of the left anterior descending coronary artery, Thereafter, animals were divided into groups: sham control, MI-untreated, MI-vehicle, and MI-A740003 (50 mg/kg/day) and treated for seven days accordingly. The heart weight/body weight ratio of untreated-ligated rats significantly increased by 15.1 %, creatine kinase-MB (CK-MB) significantly increased by 40 %, troponin-I levels significantly increased by 25.4 %, and lactate dehydrogenase significantly increased by 47.2 %, indicating myocardial damage confirmed by morphological changes and massive cardiac fibrosis. The protein expression of cardiac fibronectin, TGF-ß1, and p-Smad2 were also upregulated by 143 %, 40 %, and 8 %, respectively, indicating cardiac fibrosis. The treatment of ligated rats with A740003 led to improvement in all the above-mentioned parameters. Overall, A740003 exhibits potential cardio-protective effects on post-AMI fibrotic remodelling in the animal model of AMI through P2X7-R blockade, possibly by downregulating the profibrotic TGF-ß1/Smad signalling pathway and restoring GSK-3ß phosphorylation. Altogether, treatment with A740003 could serve as a new cardioprotective strategy to attenuate post-AMI fibrotic remodelling.

Pentoxifylline and thiamine ameliorate rhabdomyolysis-induced acute kidney injury in rats via suppressing TLR4/NF-κB and NLRP-3/caspase-1/gasdermin mediated-pyroptosis.

Acute kidney injury (AKI) is a common complication of rhabdomyolysis (RM), a syndrome characterized by skeletal muscle damage resulting in renal tubular oxidative stress, inflammation, and activated toll like receptor-4 (TLR-4) and NOD-like receptor protein-3 (NLRP-3) inflammasome. Pyroptosis is a programmed cell death mediated by NLRP-3 leading to the activation of caspase-1 and gasdermin D (GSDMD), the hallmark of pyroptosis. This study aims to investigate the renoprotective effects of two antioxidants; pentoxifylline (PTX) and thiamine (TM) via targeting the aforementioned pathways. RM-AKI was induced in male Albino Wistar rats by intramuscular injection of glycerol (50% v/v, 10 ml/kg). PTX (100 mg/kg, oral) and TM (25 mg/kg, i.p) were administered for 12 days prior glycerol injection and continued for 3 days following induction of RM-AKI. Serum creatinine, blood urea nitrogen (BUN), creatin kinase, lipid peroxides, total antioxidant activity, inflammatory markers (tumor necrosis factor-α, interleukin-1ß, and nuclear factor kappa B), TLR4, NLRP-3, caspase-1, GSDMD and c-myc (an apoptotic marker) were estimated. Compared to AKI model, co-administered drugs revealed a significant improvement in renal function and pathology as indicated by the reduction in serum creatinine, BUN and protein cast accumulation. The elevations of oxidative stress, and inflammatory markers as well as the over-expression of c-myc were alleviated. Protein levels of TLR4, NLRP3, cleaved caspase-1, and GSDMD were significantly elevated in RM-AKI model, and this elevation was attenuated by the tested drugs. In conclusion, PTX and TM could be a potential renoprotective approach for patients with RM through targeting TLR4/NF-κB and NLRP-3/caspase-1/gasdermin mediated-pyroptosis pathways.

Cardioprotective Effects of the GRK2 Inhibitor Paroxetine on Isoproterenol-Induced Cardiac Remodeling by Modulating NF-κB Mediated Prohypertrophic and Profibrotic Gene Expression.

Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the hypertrophic heart. Moreover, the expression of the G-protein-coupled receptor kinase 2 (GRK2) is increased and linked to the progression of heart failure. The inhibitory effects of paroxetine on GRK2 have been established. However, its protective effect on IκBα/NFκB signaling has not been elucidated. This study investigated the cardioprotective effect of paroxetine in an animal model of cardiac hypertrophy (CH), focusing on its effect on GRK2-mediated NF-κB-regulated expression of prohypertrophic and profibrotic genes. Wistar albino rats were administered normal saline, paroxetine, or fluoxetine, followed by isoproterenol to induce CH. The cardioprotective effects of the treatments were determined by assessing cardiac injury, inflammatory biomarker levels, histopathological changes, and hypertrophic and fibrotic genes in cardiomyocytes. Paroxetine pre-treatment significantly decreased the HW/BW ratio (p < 0.001), and the expression of prohypertrophic and profibrotic genes Troponin-I (p < 0.001), BNP (p < 0.01), ANP (p < 0.001), hydroxyproline (p < 0.05), TGF-ß1 (p < 0.05), and αSMA (p < 0.01) as well as inflammatory markers. It also markedly decreased pIκBα, NFκB(p105) subunit expression (p < 0.05) and phosphorylation. The findings suggest that paroxetine prevents pathological cardiac remodeling by inhibiting the GRK2-mediated IκBα/NF-κB signaling pathway.

Potential Effect of Baobab's Polyphenols as Antihyperlipidemic Agents: In Silico Study.

Adansonia digitata L. is an African tree commonly called baobab. This tree is effectively used in traditional medicine to treat cardiovascular disorders. Hyperlipidemia is a well-known cardiovascular risk factor associated with the increased incidence of mortality worldwide. This study aimed to demonstrate the mechanism of baobab polyphenols in the activities of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and pancreatic lipase as lipid metabolic enzymes. Molecular docking and an incentive for drug design showed that all the polyphenols in baobab bound to the proteins with higher affinity and a lower binding energy compared with simvastatin as the positive control (ΔG: from -5.5 kcal/mol to -6.5 kcal/mol). The same polyphenols exhibited a considerable binding affinity to pancreatic lipase (ΔG: from -7.5 kcal/mol to -9.8 kcal/mol) in comparison with the control and HMG-CoA reductase. Quercetin showed the best docking score from the selected Baobab polyphenols (ΔG = -9.8 kcal/mol). The root mean square deviation (RMSD) results indicated that stable epicatechin and quercetin complexes were demonstrated with HMG-CoA reductase, and other less stable complexes were developed using rutin and chlorogenic acid. Moreover, the analysis of the root mean square fluctuation (RMSF) simulation results was consistent with that of the RMSD. The RMSF value for all the baobab polyphenols, including the crystal control ligand, was kept between 0.80 and 8.00 Å, similarly to simvastatin, and less than 4.8 Å for pancreatic lipase. Chlorogenic acid, quercetin, epicatechin, and rutin had negative ΔG binding scores from highest to lowest. The same ligands displayed more negative ΔG binding scores than those observed in HMG-CoA reductase and crystal control ligand (methoxyundecyl phosphinic acid) in their simulation with pancreatic lipase. In conclusion, baobab polyphenols interact with HMG-CoA reductase and pancreatic lipase to inhibit their substrate binding and block their activity.

Expanding on the phenotypic spectrum of Woodhouse-Sakati syndrome due to founder pathogenic variant in DCAF17: Report of 58 additional patients from Qatar and literature review.

Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive neuroendocrine and ectodermal disorder caused by variants in the DCAF17 gene. In Qatar, the c.436delC variant has been reported as a possible founder pathogenic variant with striking phenotypic heterogeneity. In this retrospective study, we report on the clinical and molecular characteristics of additional 58 additional Qatari patients with WSS and compare them to international counterparts' findings. A total of 58 patients with WSS from 32 consanguineous families were identified. Ectodermal and endocrine (primary hypogonadism) manifestations were the most common presentations (100%), followed by diabetes mellitus (46%) and hypothyroidism (36%). Neurological manifestations were overlapping among patients with intellectual disability (ID) being the most common (75%), followed by sensorineural hearing loss (43%) and both ID and aggressive behavior (10%). Distinctive facial features were noted in all patients and extrapyramidal manifestations were uncommon (8.6%). This study is the largest to date on Qatari patients with WSS and highlights the high incidence and clinical heterogeneity of WSS in Qatar due to a founder variant c.436delC in the DCAF17 gene. Early suspicion of WSS among Qatari patients with hypogonadism and ID, even in the absence of other manifestations, would shorten the diagnostic odyssey, guide early and appropriate management, and avoid potential complications.

Role of Combined Na2HPO4 and ZnCl2 in the Unprecedented Catalysis of the Sequential Pretreatment of Sustainable Agricultural and Agro-Industrial Wastes in Boosting Bioethanol Production.

Improper lignocellulosic waste disposal causes severe environmental pollution and health damage. Corn Stover (CS), agricultural, and aseptic packaging, Tetra Pak (TP) cartons, agro-industrial, are two examples of sustainable wastes that are rich in carbohydrate materials and may be used to produce valuable by-products. In addition, attempts were made to enhance cellulose fractionation and improve enzymatic saccharification. In this regard, these two wastes were efficiently employed as substrates for bioethanol production. This research demonstrates the effect of disodium hydrogen phosphate (Na2HPO4) and zinc chloride (ZnCl2) (NZ) as a new catalyst on the development of the sequential pretreatment strategy in the noticeable enzymatic hydrolysis. Physico-chemical changes of the native and the pretreated sustainable wastes were evaluated by compositional analysis, scanning electron microscopy (SEM), X-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). These investigations showed major structural changes after the optimized sequential pretreatment. This pretreatment not only influences the delignification process, but also affects the functionalization of cellulose chemical structure. NZ released a higher glucose concentration (328.8 and 996.8 mg/dl) than that of ZnCl2 (Z), which released 203.8 and 846.8 mg/dl from CS and TP, respectively. This work led to the production of about 500 mg/dl of ethanol, which is promising and a competitor to other studies. These findings contribute to increasing the versatility in the reuse of agricultural and agro-industrial wastes to promote interaction areas of pollution prevention, industrialization, and clean energy production, to attain the keys of sustainable development goals.

Lignin from Agro-Industrial Waste to an Efficient Magnetic Adsorbent for Hazardous Crystal Violet Removal.

The presence of cationic dyes, even in a tiny amount, is harmful to aquatic life and pollutes the environment. Therefore, it is essential to remove these hazardous dyes to protect the life of marine creatures from these pollutants. In this research, crystal violet (CV) dye elimination was performed using a lignin copper ferrite (LCF) adsorbent. The adsorbent was synthesized and characterized using FTIR, Raman, SEM, EDX with mapping, and VSM, which proved the successful formation of magnetic LCF. Adsorption experiments were performed using different effective parameters. The highest adsorption potential (97%) was executed at mild operating conditions, with a 5 min contact time at room temperature and pH 8. The adsorption kinetic study utilized four kinetic models: first-order, second-order, intraparticle diffusion, and Elovich. The results revealed that the adsorption process complies with the pseudo-first-order with a maximum adsorption capacity of 34.129 mg/g, proving that the adsorption process mechanism is a physical adsorption process. Three isotherm models, Langmuir, Freundlich, and Temkin, were examined. The adsorption mechanism of CV onto LCF was also followed by the Langmuir and Freundlich models. The thermodynamic parameters were examined and revealed that the adsorption onto LCF was an exothermic process. It was proposed that the adsorption process is a spontaneous exothermic process. LCF appears to forcefully remove toxic CV dye from textile wastewater.

Gene therapy for spinal muscular atrophy: the Qatari experience.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by hypotonia, progressive muscle weakness, and wasting. Onasemnogene abeparvovec (Zolgensma®) is a novel gene therapy medicine, FDA-approved in May 2019 for the treatment of SMA. This study aimed to describe Qatari experience with onasemnogene abeparvovec by reviewing the clinical outcomes of 9 SMA children (7 SMA type 1 and 2 with SMA type 2) aged 4‒23 months treated between November 2019 and July 2020. Children <2 years with 5q SMA with a bi-allelic mutation in the SMN1 gene were eligible for gene therapy. Liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and total bilirubin), platelet count, coagulation profile, troponin-I levels, and motor scores (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP INTEND]), were regularly monitored following gene therapy. All patients experienced elevated AST or ALT, two experienced high prothrombin time, and one experienced elevated bilirubin; all of these patients were asymptomatic. Furthermore, one event of vomiting after infusion was reported in one patient. Significant improvements in CHOP INTEND scores were observed following therapy. This study describes the short-term outcomes and safety of onasemnogene abeparvovec, which is well tolerated and shows promise for early efficacy.

Point of Care Exome Sequencing Reveals Allelic and Phenotypic Heterogeneity Underlying Mendelian disease in Qatar.

The effectiveness of next generation sequencing at solving genetic disease has motivated the rapid adoption of this technology into clinical practice around the world. In this study, we use whole exome sequencing (WES) to assess 48 patients with Mendelian disease from 30 serial families as part of the "Qatar Mendelian Disease pilot program" - a coordinated multi-center effort to build capacity and clinical expertise in genetic medicine in Qatar. By enrolling whole families (parents plus available siblings), we demonstrate significantly improved discriminatory power for candidate variant identification over trios for both de novo and recessive inheritance patterns. For the same index cases, we further demonstrate that even in the absence of families, variant prioritization is improved up to 8-fold when a modest set of population-matched controls is used vs large public databases, stressing the poor representation of Middle Eastern alleles in presently available databases. Our in-house pipeline identified candidate disease variants in 27 of 30 families (90%), 23 of which (85%) harbor novel pathogenic variants in known disease genes, pointing to significant allelic heterogeneity and founder mutations underlying Mendelian disease in the Middle East. For 6 of these families, the clinical presentation was only partially explained by the candidate gene, suggesting phenotypic expansion of known syndromes. Our pilot study demonstrates the utility of WES for Middle Eastern populations, the dramatic improvement in variant prioritization conferred by enrolling population-matched controls and/or enrolling additional unaffected siblings at the point-of-care, and 25 novel disease-causing alleles, relevant to newborn and premarital screening panels in regional populations.

Bi-allelic TMEM94 Truncating Variants Are Associated with Neurodevelopmental Delay, Congenital Heart Defects, and Distinct Facial Dysmorphism.

Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals. The affected individuals manifested with global developmental delay/intellectual disability, and dysmorphic facial features including triangular face, deep set eyes, broad nasal root and tip and anteverted nostrils, thick arched eye brows, hypertrichosis, pointed chin, and hypertelorism. Birthweight in the upper normal range was observed in most, and all but one had congenital heart defects (CHD). Gene expression analysis in available cells from affected individuals showed reduced expression of TMEM94. Global transcriptome profiling using microarray and RNA sequencing revealed several dysregulated genes essential for cell growth, proliferation and survival that are predicted to have an impact on cardiotoxicity hematological system and neurodevelopment. Loss of Tmem94 in mouse model generated by CRISPR/Cas9 was embryonic lethal and led to craniofacial and cardiac abnormalities and abnormal neuronal migration pattern, suggesting that this gene is important in craniofacial, cardiovascular, and nervous system development. Our study suggests the genetic etiology of a recognizable dysmorphic syndrome with NDD and CHD and highlights the role of TMEM94 in early development.

The inhibitory mechanisms of losartan and vitamin D on amiodarone-induced lung inflammation in rats: Role of mitogen-activated protein kinases/activator protein-1.

Amiodarone (AMD), an antiarrhythmic drug, is used cautiously due to its lung toxicity that is characterized by alveolar inflammation followed by fatal fibrosis. AMD induces lung inflammation via increasing the alveolar macrophages and disturbing the balance of T-helper-1 (Th1) and Th2 cells cytokines. In this study, the role of the mitogen-activated protein kinases (MAPKs)/activator protein-1 (AP-1) pathway in AMD-induced lung inflammation was evaluated. Also, the anti-inflammatory and antifibrotic effects of losartan and/or vitamin D were investigated following 7, 14, and 28 days of AMD administration. AMD resulted in lung injury, inflammatory infiltration, and increased pulmonary levels of inflammatory cytokines starting from Week 1 of exposure. A significant increase in serum levels of interleukin-4 along with a significant reduction of interferon-gamma, in addition to strong expression of CD68, were reported after 14 and 28 days of AMD administration reflecting Th1/Th2 cytokines imbalance and the accumulation of alveolar macrophages, respectively. The phosphorylation of MAPKs (ERK1/2, JNK, p38) and AP-1 was significantly enhanced starting from Week 1 of exposure. Marked expression of transforming growth factor beta-1 and massive deposition of collagen were detected after 28 days reflecting late fibrosis. All these abnormalities were significantly mitigated by vitamin D and its combination with losartan. Losartan alone has less prominent anti-inflammatory effects particularly after 28 days; however, it efficiently prevented late fibrosis. This study concludes that MAPKs/AP-1 pathway is involved in AMD-induced lung inflammation and that vitamin D and/or losartan could be used as a prophylactic agent to prevent AMD-induced lung toxicity.

Upgrading of agro-industrial green biomass residues from chocolate industry for adsorption process: diffusion and mechanistic insights.

In the last decades, the world suffers from the wastes those results from unprecedented growth in the food industry. This context investigated the characteristics and suitability of utilizing cocoa shell (CS), an agro-industrial residual biomass waste from the chocolate industry, without any chemical and/or physical treatment. It is an abundant, low-cost, and green adsorbent that can be utilized for the effective removal of basic blue (BB41) as an example of cationic dye from aqueous solutions. The CS showed high adsorption potential (90.04%) with the mild operating condition, 45 min adsorption time, pH 6, CS dose 4 g/L, BB41 concentration 10 mg/L, stirring speed 400 rpm at 295 K. The kinetic, equilibrium, isotherms and mechanism studies revealed that the BB41 adsorption onto CS was attained mainly by electrostatic interaction, π-π stacking interaction, hydrogen bonding, covalent bond, and physical mechanisms. Besides, the organic functional groups played an important role during the adsorption process. The thermodynamic parameters suggested that the adsorption of BB41 dye was the non-spontaneous endothermic process with an activation energy 18.28 kJ/mol. From the industrial point of view, this work offers an economical push in waste management and also a green approach for the effective removal of toxic dyes from textile wastewater.

A founder RAB27A variant causes Griscelli syndrome type 2 with phenotypic heterogeneity in Qatari families.

Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disorder caused by pathogenic variants in the RAB27A gene and characterized by partial albinism, immunodeficiency, and occasional hematological and neurological involvement. We reviewed and analyzed the medical records of 12 individuals with GS2 from six families belonging to a highly consanguineous Qatari tribe and with a recurrent pathogenic variant in the RAB27A gene (NM_004580.4: c.244C > T, p.Arg82Cys). Detailed demographic, clinical, and molecular data were collected. Cutaneous manifestations were the most common presentation (42%), followed by neurological abnormalities (33%) and immunodeficiency (25%). The most severe manifestation was HLH (33%). Among the 12 patients, three patients (25%) underwent HSCT, and four (33%) died. The cause of death in all four patients was deemed HLH, providing evidence for this complication's fatal nature. Interestingly, two affected patients (16%) were asymptomatic. This report highlights the broad spectrum of clinical presentations of GS2 associated with a founder variant in the RAB27A gene (c.244C > T, p.Arg82Cys). Early suspicion of GS2 among Qatari patients with cutaneous manifestations, neurological findings, immunodeficiency, and HLH would shorten the diagnostic odyssey, guide early and appropriate treatment, and prevent fatal outcomes.

Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice.

Nonsense-mediated decay (NMD) is an important process that is best known for degrading transcripts that contain premature stop codons (PTCs) to mitigate their potentially harmful consequences, although its regulatory role encompasses other classes of transcripts as well. Despite the critical role of NMD at the cellular level, our knowledge about the consequences of deficiency of its components at the organismal level is largely limited to model organisms. In this study, we report two consanguineous families in which a similar pattern of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutations in SMG9, encoding an essential component of the SURF complex that generates phospho-UPF1, the single most important step in NMD. By knocking out Smg9 in mice via CRISPR/Cas9, we were able to recapitulate the major features of the SMG9-related multiple congenital anomaly syndrome we observed in humans. Surprisingly, human cells devoid of SMG9 do not appear to have reduction of PTC-containing transcripts but do display global transcriptional dysregulation. We conclude that SMG9 is required for normal human and murine development, most likely through a transcriptional regulatory role, the precise nature of which remains to be determined.

Clinical exome sequencing in 509 Middle Eastern families with suspected Mendelian diseases: The Qatari experience.

BACKGROUND: Clinical exome sequencing (CES) is rapidly becoming the diagnostic test of choice in patients with suspected Mendelian diseases especially those that are heterogeneous in etiology and clinical presentation. Reporting large CES series can inform guidelines on best practices for test utilization, and improves accuracy of variant interpretation through clinically-oriented data sharing. METHODS: This is a retrospective series of 509 probands from Qatar who underwent singleton or trio CES either as a reflex or naïve (first-tier) test from April 2014 to December 2016 for various clinical indications. RESULTS: The CES diagnostic yield for the overall cohort was 48.3% (n = 246). Dual molecular diagnoses were observed in 2.1% of cases; nearly all of whom (91%) were consanguineous. We report compelling variants in 11 genes with no established Mendelian phenotypes. Unlike reflex-WES, naïve WES was associated with a significantly shorter diagnostic time (3 months vs. 18 months, p < 0.0001). CONCLUSION: Middle Eastern patients tend to have a higher yield from CES than outbred populations, which has important implications in test choice especially early in the diagnostic process. The relatively high diagnostic rate is likely related to the predominance of recessive diagnoses (60%) since consanguinity and positive family history were strong predictors of a positive CES.

Natural history, with clinical, biochemical, and molecular characterization of classical homocystinuria in the Qatari population.

Classical homocystinuria (HCU) is the most common inborn error of metabolism in Qatar, with an incidence of 1:1800, and is caused by the Qatari founder p.R336C mutation in the CBS gene. This study describes the natural history and clinical manifestations of HCU in the Qatari population. A single center study was performed between 2016 and 2017 in 126 Qatari patients, from 82 families. Detailed clinical and biochemical data were collected, and Stanford-Binet intelligence, quality of life and adherence to treatment assessments were conducted prospectively. Patients were assigned to one of three groups, according to the mode of diagnosis: (a) late diagnosis group (LDG), (b) family screening group (FSG), and (c) newborn screening group (NSG). Of the 126 patients, 69 (55%) were in the LDG, 44 (35%) in the NSG, and 13 (10%) in the FSG. The leading factors for diagnosis in the LDG were ocular manifestations (49%), neurological manifestations (45%), thromboembolic events (4%), and hyperactivity and behavioral changes (1%). Both FSG and NSG groups were asymptomatic at time of diagnosis. NSG had significantly higher intelligence quotient, quality of life, and adherence values compared with the LDG. The LDG and FSG had significantly higher methionine levels than the NSG. The LDG also had significantly higher total homocysteine levels than the NSG and FSG. Regression analysis confirmed these results even when adjusting for age at diagnosis, current age, or adherence. These findings increase the understanding of the natural history of HCU and highlight the importance of early diagnosis and treatment. SYNOPSIS: A study in 126 Qatari patients with HCU, including biochemical, clinical, and other key assessments, reveals that patients with a late clinical diagnosis have a poorer outcome, hereby highlighting the importance of early diagnosis and treatment.

Correction to: Expanding the genetic heterogeneity of intellectual disability.

Variant nomenclature discrepancy was identified in the article.

Expanding the genetic heterogeneity of intellectual disability.

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.

W44X mutation in the WWOX gene causes intractable seizures and developmental delay: a case report.

BACKGROUND: WW domain containing oxidoreductase (WWOX) gene was cloned in 2000; alteration has been seen in many cancer cells. It acts as a tumor suppresser by blocking cell growth and causing apoptosis. WWOX protein showed different expression of mice brain and spinal cord, for which deletion causes seizure and early death. CASE PRESENTATION: Clinical and molecular characteristics of a consanguineous family show a homozygous mutation of WWOX gene at specific bases, causing a debilitating syndrome characterized by growth retardation, intractable epilepsy, intellectual disability, and early death. Using Whole Exome Sequencing (WES), a novel homozygous mutation in the WWOX gene is identified in a consanguineous Arab family from Qatar with two daughters who presented with intractable seizure and developmental delay. CONCLUSION: The study presents the importance of human WWOX gene for brain development and the association between gene mutation and epileptic encephalopathy. It also highlights the power of WES particularly in clinically challenging cases.

High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders.

Clinical exome sequencing (CES) has become an increasingly popular diagnostic tool in patients with heterogeneous genetic disorders, especially in those with neurocognitive phenotypes. Utility of CES in consanguineous populations has not yet been determined on a large scale. A clinical cohort of 149 probands from Qatar with suspected Mendelian, mainly neurocognitive phenotypes, underwent CES from July 2012 to June 2014. Intellectual disability and global developmental delay were the most common clinical presentations but our cohort displayed other phenotypes, such as epilepsy, dysmorphism, microcephaly and other structural brain anomalies and autism. A pathogenic or likely pathogenic mutation, including pathogenic CNVs, was identified in 89 probands for a diagnostic yield of 60%. Consanguinity and positive family history predicted a higher diagnostic yield. In 5% (7/149) of cases, CES implicated novel candidate disease genes (MANF, GJA9, GLG1, COL15A1, SLC35F5, MAGE4, NEUROG1). CES uncovered two coexisting genetic disorders in 4% (6/149) and actionable incidental findings in 2% (3/149) of cases. Average time to diagnosis was reduced from 27 to 5 months. CES, which already has the highest diagnostic yield among all available diagnostic tools in the setting of Mendelian disorders, appears to be particularly helpful diagnostically in the highly consanguineous Middle Eastern population.