Mashael Al-Shafai

Populations of Arab ancestry remain underrepresented in global twin studies. These populations are described by distinct genetic characteristics, high consanguinity, and strong familial relatedness. To contribute to diversity in genetics and twin research, the Qatar Twin Registry (QTR) was established as the first national twin registry in the Arab world and the second in the Middle East and North Africa. The QTR is a prospective and retrospective cohort study developed by Qatar University in collaboration with the Qatar Precision Health Institute (QPHI). The registry integrates with Qatar’s national biobank and whole-genome sequencing infrastructure to enable large-scale twin-based research. Participants contribute comprehensive health, developmental, psychosocial, and lifestyle information, along with biological samples collected through clinic-based assessments and home visits. QTR marks a milestone in regional genetic and epidemiological research. Leveraging and linking to Qatar’s national biobank and genomic infrastructure, it establishes a sustainable framework for investigating heritability, gene–environment interactions, and complex diseases in an underrepresented Arab population, contributing to global precision medicine efforts.

Premarital screening (PMS) programs have been increasingly implemented in various countries due to their potential to reduce the incidence of genetic condi

Circadian rhythms disruption causes clustering of metabolic disorders and depression. The comorbidity of depression and obesity is common and could be attr

Non-syndromic Inherited Retinal Dystrophies (IRDs) are a set of degenerative retinal diseases that vary clinically and genetically, including Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). IRDs are a significant cause of vision loss in young adults globally. To date, more than 280 genes have been associated with IRD pathogenesis. This study aims to investigate the genetic basis of non-syndromic IRD in the Qatari population and to assess the diagnostic yield of various genetic tests through a retrospective cohort study. Our study identified 49 eligible patients with IRD, 61.2% of whom were Qatari. Rod-dominated phenotypes accounted for 51% of the hereditary retinal diseases in this cohort. Whole-exome sequencing with mitochondrial genome testing (WES Plus) was the most frequently utilized genetic test. A total of 55 variants were identified across 32 IRD-associated genes. Of the 49 cases, 34 (69.4%) were initially classified as solved, and an additional five were likely to be solved based on familial segregation analysis. Variants in the ABCA4 gene were the most commonly observed, present in eight patients, with the c.5882G>A variant being the most recurrent, identified in three of these cases. Specific genes exhibited recurrent variations, including pan-ethnic variants that are common across multiple populations. These variants merit prioritization in testing due to their global prevalence. WES is recommended as a first-tier test for non-syndromic IRD cases, as it accelerates diagnosis, facilitates earlier interventions, and provides a comprehensive genetic picture by incorporating information from family members. Moreover, our study highlighted the significance of performing family segregation analyses in identifying possible causative variants. This is the first genetic study of IRD in Qatar, laying the groundwork for further research on the epidemiology and genetics of non-syndromic IRD in this understudied region.

Bariatric metabolic surgery (BMS) is a common intervention for severe obesity, yet its effects on cancer risk remain unclear. Observational studies and meta-analyses yield inconsistent findings, while randomized controlled trials often lack adequate follow-up to evaluate cancer outcomes. This study aims to emulate a target trial using observational data, employing a transparent and robust methodology to address this issue. We constructed a large retrospective cohort of adults with obesity in Qatar using electronic medical records from the public health system, with data available from 2018. We developed and applied iterative time distribution matching (ITDM) which is an iterative version of prescription time distribution matching (PTDM) as an improved approach to mitigate immortal time bias. This adaptation facilitated the alignment of time-zero (T0) between BMS recipients and non-recipients. Subsequently, we applied a Cox proportional hazards regression model, controlling for confounders and prognostic covariates, for data analysis. The final study cohort comprised 124,780 individuals aged 30 years and older, including 1,465 who underwent BMS and 1,583 who developed cancer during the follow-up period. The median follow-up duration was 7.79 years (IQR: 4.89–10.85). In the confounder- and prognostic covariate-adjusted Cox model, BMS was associated with a reduced hazard of cancer (HR 0.49, 95% CI 0.31 to 0.76). Given potential residual confounding and the limited outcome data, these findings provide preliminary evidence of a protective association and should be interpreted cautiously. This approach emphasizes transparency in trial emulation design, and future studies should focus on specific cancer types and long-term outcomes as additional data become available.

Background: Newborn screening is an essential public health strategy that aims to detect a range of conditions, including inborn errors of metabolism, in neonates shortly after birth. The timely identification is crucial due to the asymptomatic nature of many conditions at birth, but which can lead to significant health complications if left untreated. Through this study, we aimed to investigate the incidence of IEMs screened by the Qatar National Newborn Screening Program. Methods: We retrospectively analyzed a total of 351,223 newborns screened from 2010 to 2023. The incidence for the studied IEMs was calculated and correlated with demographics, consanguinity, and family history. In addition, the diagnostic yield of different tests utilized was assessed. Results: Our study revealed a total of 318 positive cases with IEMs, and a significantly high incidence of 1:1105 for IEMs in Qatar. Classical Homocystinuria was the most frequently detected condition, with a cumulative incidence of 1:6754 live births, linked to the founder variant p. Arg336Cys in the CBS gene. Aminoacidopathies were the most prevalent category, followed by fatty acid oxidation disorders, organic acidurias, biotinidase deficiency, and urea cycle disorders. Genetic testing showed a high diagnostic yield of 90%. Of the 60 cases that underwent targeted variant testing, 98% were confirmed, while 90% of the 59 cases tested by single gene testing were confirmed. Conclusions: Our study provides the incidence rates of IEMs in Qatar and novel insights that could facilitate setting up/developing IEM incidence-reducing strategies and improving outcomes for affected newborns and their families.

Cardiovascular diseases (CVDs) remain a leading cause of global morbidity and mortality. Metabolomics allows for the identification of important biomarkers for CVDs, essential for early detection and risk assessment. This cross-sectional study aimed to identify novel metabolic biomarkers associated with CVDs using non-targeted metabolomics. We compared the metabolic profiles of 112 patients with confirmed CVDs diagnosis and 112 gender- and age-matched healthy controls from the Qatar Biobank database. Orthogonal partial least square discriminate analysis and linear models were used to analyze differences in the level of metabolites between the two groups. We report here a significant association between the indoleacetylglutamine pathway and cardiovascular diseases, expanding the repertoire of gut microbiota metabolites linked to CVDs. Our findings suggest that alterations in gut microbiota metabolism, potentially resulting in increased production of indoleacetate, indoleacetylglutamine, and related compounds at the expense of the cardioprotective indolepropionate, may contribute to this association. Our findings may pave the way for novel approaches in CVD risk assessment and potential therapeutic interventions targeting the gut-heart axis.

GNAS (Guanine Nucleotide-Binding Protein, Alpha Stimulating) is a complex gene that encodes the alpha subunit of the stimulatory G protein (G_sα), critical for signaling through various G protein-coupled receptors. Inactivating genetic and epigenetic changes in GNAS, resulting in G_sα deficiency, cause different variants of pseudohypoparathyroidism, which may manifest features of Albright hereditary osteodystrophy (AHO, a syndrome characterized by early-onset obesity and other developmental defects). Recent findings have linked G_sα deficiency with isolated, severe, early-onset obesity, suggesting it as a potential, underrecognized cause of monogenic, non-syndromic obesity. This study was prompted by identifying several GNAS variants of uncertain significance (VUSs) in pediatric patients presenting with unexplained, severe, early-onset obesity at Sidra Medicine in Qatar. To functionally characterize these variants, we developed the first zebrafish model of G_sα deficiency, offering numerous advantages over other model systems. This was achieved by knockdown of the ortholog through microinjection of translation-blocking Morpholino antisense oligonucleotides into the yolks of 1-8-cell-stage zebrafish embryos. The morphant larvae displayed an obese phenotype, marked by significantly enlarged yolk sacs, increased neutral lipid accumulation, and reduced metabolic rates, among other developmental abnormalities resembling those in AHO. This zebrafish model lays the foundation for efficient functional characterization of GNAS VUSs and paves the way for enhancing our understanding of G_sα deficiency-associated early-onset obesity.

The kinase suppressor of Ras 2 (KSR2) gene is associated with monogenic obesity, and loss-of-function variants in KSR2 have been identified in individuals with severe early-onset obesity. This study investigated KSR2 variants in 9 pediatric patients with severe early-onset obesity in Qatar using whole genome sequencing among a cohort of 240 individuals. We focused on KSR2 variants with a minor allele frequency (MAF) below 1% and a Combined Annotation Dependent Depletion (CADD) score above 13 to identify potential causative variants. Our analysis identified four KSR2 variants: one intronic (c.1765-8G>A) and three missense variants (c.1057G>A, c.1673G>A, and c.923T>C) in nine patients. The intronic variant c.1765-8G>A was the most frequent (seen in six individuals) and had a CADD score of 21.10, suggesting possible pathogenicity. This variant showed a significantly higher allele frequency in the Qatari population compared to the Genome Aggregation Database (gnomAD), indicating a possible founder effect. Molecular modeling of the missense variants revealed structural changes in the protein structure. The study concludes that these four KSR2 variants are associated with monogenic obesity, with an autosomal dominant inheritance pattern. The c.1765-8G>A variant’s prevalence in Qatar underscores its importance in genetic screening for severe obesity. This research advances the understanding of genetic factors in severe early-onset obesity and may inform better management strategies.