Severe Transfusion-Dependent Thalassemia in Compound Heterozygote Palestinian Siblings with Two α-Globin Gene Defects, Hb Taybe D HBA1: C.119_121delCCA Mutation and HBA2: C.*94A > G Mutation.

Alpha and Beta Thalassemia are autosomal recessive anemias that cause significant morbidity and mortality worldwide, especially in the Middle East and North Africa (MENA) region where carrier rates reach up to 50%. We report the case of two siblings of Palestinian origin born who presented to our tertiary healthcare center for the management of severe transfusion dependent hemolytic anemia. Before presentation to our center, the siblings were screened for a-thalassemia using the Alpha-globin StripAssay. They were found to carry the α2 polyA-1 [AATAAA > AATAAG] mutation in the heterozygous form, which was insufficient to make a diagnosis. No pathogenic variants were detected on Sanger sequencing of the HBB gene. Full sequencing of the a-gene revealed compound heterozygous variants (HBA1:c.119_121delCCA and the previously detected HBA2:c.*+94A > G Poly A [A->G]) with trans inheritance. This report highlights the impact of non-deletional mutations on α-globin chain stability. The compound heterozygosity of a rare α-globin chain pathogenic variant with a polyadenylation mutation in the probands leads to clinically severe a-thalassemia. Due to the high carrier status, the identification of rare mutations through routine screening techniques in our populations may be insufficient. Ongoing collaboration among hematologists, medical geneticists, and counselors is crucial for phenotypic-genotypic correlation and assessment of adequate genetic testing schemes.

Genetic literacy among primary care physicians in a resource-constrained setting.

BACKGROUND: Genetic literacy among primary healthcare providers is crucial for appropriate patient care with the advances in genetic and genomic medicine. Studies from high-income countries highlight the lack of knowledge in genetics and the need to develop curricula for continuing professional development of non-geneticists. Scarce data is available from resource-constrained countries in Middle East and North Africa. Lebanon is a small country in this region characterized by high rates of consanguinity and genetic disorders like several surrounding countries, such as Jordan, Syria, and Turkey. METHODS: The primary aim of this study assessed the genetic literacy, self-perceived and actual knowledge as well as practices among primary care providers in Lebanon. The secondary aim identified their educational needs and proposed evidence-based continuing education programs. A cross-sectional survey-based study, using a self-administered questionnaire, was conducted targeting physicians from Family Medicine, Obstetrics and Gynecology, and Pediatrics. The questionnaire was divided into five sections: demographics, familiarity with genetic tests, self-reported and actual knowledge, genetic practices, and educational needs. Statistics were performed using SPSS v24. The Chi-square test was used for independent variables. Differences between mean scores were measured using paired sample t-tests for groups of two levels and one-way ANOVA for more than two. Multiple linear regression was used to study the variables associated with the knowledge score while controlling for other variables. RESULTS: The survey included 123 physicians. They were mostly familiar with karyotype as first-tier genetic test. Although 38% perceived their knowledge as good, only 6% scored as such in knowledge assessment. A better knowledge score was observed in academic institutions as well as in urban settings (p<0.05). One third never ordered any genetic testing, mostly due to poor knowledge. Almost all (98%) were ready to attend continuing professional development sessions in genetics. CONCLUSION: Our findings show the need to improve genetic literacy among healthcare frontliners, focusing on remote regions and nonacademic centers in Lebanon, a model for other resource-constrained country in the Middle East and North Africa region. This study advances recommendations for evidence-based genetic continuing education programs and highlighted the role of that the few genetic specialists can play in their successful implementation.

Interventions addressing genetic disease burdens within selected countries in the MENA region: a scoping review.

BACKGROUND: The MENA region is disproportionately affected by genetic disease. The aim of this research is to scope the region for evidence of genetic services and public health interventions to identify geographic gaps, and to provide a descriptive overview of interventions to identify knowledge gaps. METHODS: This study is conducted as a scoping review and follows the Arksey & O'Malley scoping review framework. RESULTS: Seventy-six articles spanning 16 MENA nations met inclusion criteria. Studies included interventions in the form of genetic service provision (n=28), as well as comprehensive programs including pilot programs (n=7), community-based genetics programs (n=6) national-level prevention programs (n=18), and national-level mandatory programs (n=17). CONCLUSIONS: There is an imbalanced response to genetic disease burdens across the MENA region. More research is warranted where interventions are scarce, particularly to inform development of pilot community-based programs. There is also a need for better monitoring and evaluation of existing nation-wide programs.

Molecular prevalence of eight different sexually transmitted infections in a Lebanese major tertiary care center: impact on public health.

BACKGROUND: Sexually transmitted diseases (STD) are caused by a variety of pathogens transmitted by sexual activity. Untreated infections can cause major complications with a substantial high cost on health sector. With the development of molecular techniques, STD screening became easier with a high sensitivity and specificity. OBJECTIVES: In Lebanon, official data regarding STD trends are scarce. This study elucidates the STD molecular profile at a tertiary care center, American University of Beirut Medical Center (AUBMC), its distribution among gender and age groups, with a comparison to international studies. METHODS: A retrospective data analysis was conducted on all STD panels performed at AUBMC from January 2017 till December 2019 to determine the molecular prevalence of eight different sexually transmitted organisms. RESULTS: Our samples belonged to 248 females (41.5%) and 349 males (58.5%). Only 53.5% of the samples tested positive for one or more organisms. Ureaplasma urealyticum/parvum was found to be the most common pathogen (49.3%), followed by Gardenerella vaginalis (33.5%), Chlamydia trachomatis (5.36%), Mycoplasma genitalium (5.16%), Neisseria gonorrhea (2.5%), Herpes simplex virus (2.5%), and Trichomonas vaginalis (1.39%). Age was distributed between 5 and 80 years old. Regarding the pathogen's distribution among gender, Ureaplasma urealyticum/parvum, Herpes simplex virus, and Gardenerella vaginalis were more common in females, the rest was more detected in males. CONCLUSION: Data will be of great importance for clinicians, in terms of diagnosis and treatment. It will help adopting an evidence based STI control programs in Lebanon, and it is essential for future larger studies and sexual health awareness programs.

Recommended measures for the efficient care of patients with genetic disorders during the COVID-19 pandemic in low and middle income countries.

The coronavirus disease 2019 (COVID-19) emerged in early 2020 and since, has brought about tremendous cost to economies and healthcare systems universally. Reports of pediatric patients with inherited conditions and COVID-19 infections are emerging. Specific risks for morbidity and mortality that this pandemic carries for different categories of genetic disorders are still mostly unknown. Thus, there are no specific recommendations for the diagnosis, management, and treatment of patients with genetic disorders during the COVID-19 or other pandemics. Emerging publications, from Upper-Middle Income countries (UMIC), discuss the recent experiences of genetic centers in the continuity of care for patients with genetic disorders in the context of this pandemic. Many measures to facilitate the plan to continuous genetic care in a well-developed health system, may not be applicable in Low and Middle Income countries (LMIC). With poorly structured health systems and with the lack of established genetic services, the COVID-19 pandemic will easily exacerbate the access to care for patients with genetic disease in these countries. This article focuses on the unique challenges of providing genetic healthcare services during emergency situations in LMIC countries and provides practical preparations for this and other pandemic situations.

Mapping the Diverse Genetic Disorders and Rare Diseases Among the Syrian Population: Implications on Refugee Health and Health Services in Host Countries.

The aim of this systematic review is to provide physicians and researchers with a comprehensive list of reported genetic disorders in patients of Syrian origin-those who have become part of the largest displaced population globally-and to highlight the need to consider migrant population-based risk for the development of genetic disease control and prevention programs. This review was performed based on the 2015 PRISMA and the international prospective register of systematic reviews. The present review reports on a total of 166 genetic disorders (only 128 reported on OMIM) identified in the Syrian population. Of these disorders, 27% are endocrine-, nutritional- and metabolic-related diseases. Second to metabolic disorders are congenital malformations, deformations and chromosomal abnormalities. Diseases of the blood and the blood-forming organs accounted for 13% of the total genetic disorders. The majority of the genetic disorders reported in Syrian patients followed an autosomal recessive mode of inheritance. These findings are a reflection of the high rates of consanguineous marriages that favor the increase in incidence of these diseases. From the diseases that followed an autosomal recessive mode of inheritance, 22% are reported to be only present in Syria and other regional countries. Twelve of these genetic diseases were identified to be strictly diagnosed in individuals of Syrian origin. The present systematic review highlights the need to develop programs that target genetic disorders affecting Syrian migrants in host countries. These programs would have potential financial and economic benefits, as well as a positive impact on the physical and mental health of members of the Syrian refugee community and those of their host societies. In turn, this would decrease the burden on the health systems in host countries.

SLC35B4, an Inhibitor of Gluconeogenesis, Responds to Glucose Stimulation and Downregulates Hsp60 among Other Proteins in HepG2 Liver Cell Lines.

SLC35B4, solute receptor for UDP-N-acetylglucosamine and UDP-xylose, is associated with diabetes and predisposing conditions. This study investigated the localization of SLC35B4 and compared the differential expression between a knockdown of SLC35B4 and controls in HepG2. Responsiveness to glucose, expression, and localization were assayed using Western blot and immunostaining. Localization was confirmed using a proximity ligation assay. Two-dimensional (2D) gel electrophoresis and MALDI-TOF were used to identify differentially expressed proteins and pathway analysis was performed. SLC35B4 was increased by 60% upon glucose stimulation and localized in Golgi apparatus and endoplasmic reticulum. Presence of SLC35B4 in the Golgi apparatus suggests its involvement in the biosynthesis of glycoconjugate proteins. Four proteins were markedly under-expressed (Hsp60, HspA8, TUBA1A, and ENO1) and linked to the pathogenesis of diabetes or post-translationally modified by O-GlcNAc. Glucose levels activate SLC35B4 expression. This triggers a downstream effect via Hsp60 and other proteins. We hypothesize that the downstream effect on the proteins is mediated via altering the glycosylation pattern inside liver cells. The downstream cascade ultimately alters the ability of cultured liver cells to inhibit endogenous glucose production, and this could play a role in the association of the above-listed genes with the pathogenesis of diabetes.

Does published research on non-communicable disease (NCD) in Arab countries reflect NCD disease burden?

OBJECTIVES: To review trends in non-communicable (NCD) research output in the Arab region, in terms of quantity and quality, study design, setting and focus. We also examined differences by time and place, and assessed gaps between research output and NCD burden. METHODS: A scoping review of a total of 3,776 NCD-related reports published between 2000 and 2013 was conducted for seven Arab countries. Countries were selected to represent diverse socio-economic development levels in the region: Regression analyses were used to assess trends in publications over time and by country. Research gaps were assessed by examining the degree of match between proportionate literature coverage of the four main NCDs (CVD, cancer, DM, and COPD) and cause-specific proportional mortality rates (PMR). RESULTS: The annual number of NCD publications rose nearly 5-fold during the study period, with higher income countries having the higher publication rates (per million populations) and the most rapid increases. The increase in the publication rate was particularly prominent for descriptive observational studies, while interventional studies and systematic reviews remained infrequent (slope coefficients = 13.484 and 0.883, respectively). Gap analysis showed a mismatch between cause-specific PMR burden and NCD research output, with a relative surplus of reports on cancer (pooled estimate +38.3%) and a relative deficit of reports on CVDs (pooled estimate -30.3%). CONCLUSION: The widening disparity between higher and lower-income countries and the discordance between research output and disease burden call for the need for ongoing collaboration among Arab academic institutions, funding agencies and researchers to guide country-specific and regional research agendas, support and conduct.

Mapping genetic research in non-communicable disease publications in selected Arab countries: first step towards a guided research agenda.

BACKGROUND: In the Arab world, intervention and policy response to non-communicable diseases (NCD) has been weak despite extensive epidemiological evidence highlighting the alarmingly increased prevalence of chronic diseases. Generating genetic information is one key component to promote efficient disease management strategies. This study undertook a scoping review to generate the profile of the undertaken research on genetics of NCD publications in selected Arab countries. An analysis of the research produced examined the extent, range, nature, topic and methods of published research. The study aimed at identifying the gaps in genetic NCD research to inform policy action for NCD prevention and control. METHODS: The scoping review was conducted based on the five-stage methodological framework and included countries in Arab region selected to represent various economies and epidemiological transitions. RESULTS: The search identified 555 articles that focus on genetics-NCD research in the selected Arab countries over the duration of this study (January 2000 to December 2013). The most commonly conducted research was descriptive and clinically focused, rather than etiologically focused. Country-specific carrier and risk screening studies were not among the top research designs. The genetic component of certain highly heritable diseases, as well as diabetes, obesity, hypertension, chronic lung dysfunction and metabolic syndrome were all under investigated. CONCLUSIONS: This scoping review identified gaps for further research in the context of bioinformatics and genome-wide association studies. Genetic research in the Arab region has to be redirected towards NCDs with the highest morbidity, heritability and health burden within each country. A focused research plan to include community genetics is required for its proper integration in the Arab community.

Hepatitis E virus in the countries of the Middle East and North Africa region: an awareness of an infectious threat to blood safety.

PURPOSE: Hepatitis E virus (HEV) is mainly transmitted through contaminated water supplies which make the virus endemic in developing countries including countries of the Middle East and North Africa (MENA) region. Recent reports suggest potential risk of HEV transmission via blood transfusion. METHODS: Related articles on HEV were collected by searching through the 25 countries of the MENA region using Pubmed and Medline within the past 14 years: January 2000-August 2014. RESULTS: One hundred articles were extracted, of which 25 were not eligible. The articles discussed the seroprevalence of HEV and HEV markers in 12 countries. Eight articles provided data on HEV in blood donors. The seroprevalence of HEV in the general MENA population ranged from 2.0 to 37.5% and was higher in males than in females. Prevalence increased with age, but exposure seems to be in early life. CONCLUSIONS: In the MENA region, the role of HEV as an infectious threat to blood safety is under-investigated. More data are needed to quantify the risk of transmission and to assess clinical outcomes. This requires, at least, surveillance screening of donors and recipients for HEV markers using sensitive and specific serological tests. At the present time, serious consideration should be given to selective screening for certain groups of patients (e.g., immunocompromised, pregnant women and others) who commonly require blood transfusion and are at high risk of hepatic failure or chronicity from HEV infection.

A review of the diverse genetic disorders in the Lebanese population: highlighting the urgency for community genetic services.

The review lists the genetic diseases reported in Lebanese individuals, surveys genetic programs and services, and highlights the absence of basic genetic health services at the individual and community level. The incidence of individual diseases is not determined, yet the variety of genetic diseases reported is tremendous, most of which follow autosomal recessive inheritance reflecting the social norms in the population, including high rates of consanguinity, which favor the increase in incidence of these diseases. Genetic services including all activities for the diagnosis, care, and prevention of genetic diseases at community level are extremely inadequate. Services are limited to some clinical and laboratory diagnostic services with no genetic counseling. These services are localized within the capital thus preventing their accessibility to high-risk communities. Screening programs, which are at the core of public health prevention services, are minimal and not nationally mandated. The absence of adequate genetic services is attributed to many factors undermining the importance of genetic diseases and their burden on society, the most important of which is genetic illiteracy at all levels of the population, including high-risk families, the general public, and most importantly health care providers and public health officials. Thus, a country like Lebanon, where genetic diseases are expected to be highly prevalent, is in utmost need for community genetics services. Strategies need to be developed to familiarize public health officials and medical professionals with medical genetics leading to a public health infrastructure that delivers community genetics services for the prevention and care of genetic disorders at community level.

Natural Killer Cell Immunoglobulin-like Receptor (KIR) genotypes in Follicular Lymphoma patients: results of a pilot study.

AIMS: The Natural Killer Cell Immunoglobulin-like Receptor (KIR) genotype profiling in Follicular Lymphoma has not been reported before in the literature. MATERIALS AND METHODS: DNA extracted from 20 Follicular Lymphoma patients and 62 healthy controls was analyzed for KIR genotyping using a polymerase chain reaction/sequence specific primers technique (PCR/SSP) for the presence of 16 KIR gene and pseudogene loci. RESULTS: The AA, AB, and BB genotype frequencies were, respectively, 20%, 60% and 20% with an A:B ratio of 1:1. KIR 2DL4, KIR 3DL2, KIR 3DL3, and KIR 3DP1*003 were presented in all individuals. No significant difference between patients and controls was detected. CONCLUSION: KIR genotyping profile does not seem to be associated with Follicular Lymphoma. The results presented in this pilot research represent the first international report about this important clinical entity.

Deep congenic analysis identifies many strong, context-dependent QTLs, one of which, Slc35b4, regulates obesity and glucose homeostasis.

Although central to many studies of phenotypic variation and disease susceptibility, characterizing the genetic architecture of complex traits has been unexpectedly difficult. For example, most of the susceptibility genes that contribute to highly heritable conditions such as obesity and type 2 diabetes (T2D) remain to be identified despite intensive study. We took advantage of mouse models of diet-induced metabolic disease in chromosome substitution strains (CSSs) both to characterize the genetic architecture of diet-induced obesity and glucose homeostasis and to test the feasibility of gene discovery. Beginning with a survey of CSSs, followed with genetic and phenotypic analysis of congenic, subcongenic, and subsubcongenic strains, we identified a remarkable number of closely linked, phenotypically heterogeneous quantitative trait loci (QTLs) on mouse chromosome 6 that have unexpectedly large phenotypic effects. Although fine-mapping reduced the genomic intervals and gene content of these QTLs over 3000-fold, the average phenotypic effect on body weight was reduced less than threefold, highlighting the "fractal" nature of genetic architecture in mice. Despite this genetic complexity, we found evidence for 14 QTLs in only 32 recombination events in less than 3000 mice, and with an average of four genes located within the three body weight QTLs in the subsubcongenic strains. For Obrq2a1, genetic and functional studies collectively identified the solute receptor Slc35b4 as a regulator of obesity, insulin resistance, and gluconeogenesis. This work demonstrated the unique power of CSSs as a platform for studying complex genetic traits and identifying QTLs.

Increased mitochondrial oxidative phosphorylation in the liver is associated with obesity and insulin resistance.

Obesity is the result of excess energy intake relative to expenditure, however little is known about why some individuals are more prone to weight gain than others. Inbred strains of mice also vary in their susceptibility to obesity and therefore represent a valuable model to study the genetics and physiology of weight gain and its co-morbidities such as type 2 diabetes. C57BL/6J mice are susceptible to obesity and insulin resistance when fed an obesogenic diet, whereas A/J mice are resistant despite increased caloric intake. Analysis of B6- and A/J-derived chromosome substitution strains and congenic strains revealed a complex genetic and physiological basis for this phenotype. To improve our understanding of the molecular mechanisms underlying susceptibility to metabolic disease we analyzed global gene expression patterns in 6C1 and 6C2 congenic strains. 6C1 is susceptible whereas 6C2 is resistant to diet-induced obesity. In addition, we demonstrate that 6C1 is glucose intolerant and insulin resistant relative to 6C2. Pathway analysis of global gene expression patterns in muscle, adipose, and liver identified expression level differences between 6C1 and 6C2 in pathways related to basal transcription factors, endocytosis, and mitochondrial oxidative phosphorylation (OxPhos). The OxPhos expression differences were subtle but evident in each complex of the electron transport chain and were associated with a marked increase in mitochondrial oxidative capacity in the livers of the obese strain 6C1 relative to the obesity-resistant strain 6C2. These data suggests the importance of hepatic mitochondrial function in the development of obesity and insulin resistance.

Ancestral paternal genotype controls body weight and food intake for multiple generations.

Current treatments have largely failed to slow the rapidly increasing world-wide prevalence of obesity and its co-morbidities. Despite a strong genetic contribution to obesity (40-70%), only a small percentage of heritability is explained with current knowledge of monogenic abnormalities, common sequence variants and conventional modes of inheritance. Epigenetic effects are rarely tested in humans because of difficulties arranging studies that distinguish conventional and transgenerational inheritance while simultaneously controlling environmental factors and learned behaviors. However, growing evidence from model organisms implicates genetic and environmental factors in one generation that affect phenotypes in subsequent generations. In this report, we provide the first evidence for paternal transgenerational genetic effects on body weight and food intake. This test focused on the obesity-resistant 6C2d congenic strain, which carries the Obrq2a(A/J) allele on an otherwise C57BL/6J background. Various crosses between 6C2d and the control C57BL/6J strain showed that the Obrq2a(A/J) allele in the paternal or grandpaternal generation was sufficient to inhibit diet-induced obesity and reduce food intake in the normally obesity-susceptible, high food intake C57BL/6J strain. These obesity-resistant and reduced food intake phenotypes were transmitted through the paternal lineage but not the maternal lineage with equal strength for at least two generations. Eliminating social interaction between the father and both his offspring and the pregnant dam did not significantly affect food intake levels, demonstrating that the phenotype is transmitted through the male germline rather than through social interactions. Persistence of these phenotypes across multiple generations raises the possibility that transgenerational genetic effects contribute to current metabolic conditions.

Resistance to diet-induced obesity in mice with a single substituted chromosome.

Obesity and its comorbidities are taking an increasing toll on human health. Key pathways that were identified with single gene variants in humans and model organisms have led to improved understanding and treatment of rare cases of human obesity. However, similar progress remains elusive for the more common multifactorial cases of metabolic dysfunction and disease. A survey of mouse chromosome substitution strains (CSSs) provided insight into the complex genetic control of diet-induced obesity and related conditions. We now report a survey of 60 traits related to obesity and metabolic syndrome in mice with a single substituted chromosome as well as selected traits measured in congenic strains derived from the substituted strain. We found that each strain that was resistant to diet-induced obesity had a distinct phenotype that uniquely modeled different combinations of traits related to metabolic disease. For example, the chromosome 6 CSS remained insulin resistant in the absence of obesity, demonstrating an atypical relationship between body weight and insulin resistance. These results provide insights into the genetic control of constant components of this mouse model of diet-induced metabolic disease as well as phenotypes that vary depending on genetic background. A better understanding of these genotype-phenotype relationships may enable a more individualized diagnosis and treatment of obesity and the metabolic syndrome.