Spectrum of genetic disorders and gene variants in the United Arab Emirates national population: insights from the CTGA database

**Background:** The United Arab Emirates (UAE) has a high prevalence of genetic disorders, partly due to a consanguinity rate of approximately 50% and the presence of isolated populations. The Catalogue for Transmission Genetics in Arabs (CTGA) is an open-access database that compiles bibliographic data on human gene variants associated with inherited phenotypes in Arab populations. This study provides the first comprehensive review and analysis of all genetic disorders and gene variants reported exclusively in Emirati nationals and hosted on CTGA.

**Methods:** A literature search was conducted for biomedical literature from 2010 to 2021 using PubMed and Google Scholar. Inclusion criteria were articles describing a genetic disease or phenotype in Emirati individuals and articles describing genetic variants in Emirati individuals or the population. Exclusion criteria included articles where ethnicity could not be confirmed and redundant data. Relevant information was curated onto CTGA, including clinical features, diagnosed conditions, genetic variants, and bibliographic sources. Data were standardized using Human Phenotype Ontology (HPO) terms, OMIM records, and HGVS nomenclature. Variant clinical significance was recorded from the literature (CTGA CS) and compared with ClinVar.

**Key Results:** Out of 15,599 surveyed articles, 334 relevant publications were curated, bringing the total UAE-related papers on CTGA to 487. The database includes 11,875 Emirati subjects diagnosed with 665 different genetic disorders/phenotypes. Of these, 93.4% follow a purely genetic inheritance pattern. Autosomal recessive disorders account for nearly two-thirds of non-multifactorial conditions, and over 95% of patients with autosomal recessive transmission had consanguineous parents. The database describes 1,365 variants in 844 genes; 74% are substitutions, 10% deletions, and 6% reference alleles. Notably, 235 variants (17.2%) are exclusive to CTGA and absent from dbSNP and ClinVar. Additionally, 55 variants classified as pathogenic/likely pathogenic on CTGA are marked as benign, VUS, or lack clinical significance on ClinVar. Ten disorders have been reported exclusively in Emirati patients, and 13 genetic disorders were first mapped in Emirati families. Disorders reported in at least 30 families include Cystic Fibrosis, Beta-Thalassemia, and Sickle Cell Anemia. Globally rare diseases such as Stuve-Wiedemann Syndrome, Stargardt Disease 1, Biotinidase Deficiency, and Phenylketonuria were reported in more than ten families each.

**Clinical Implications:** The high prevalence of autosomal recessive disorders underscores the impact of consanguinity and the need for targeted genetic counseling and screening programs. The identification of founder variants, such as the LIFR c.653dup variant found in 50 children from 28 families with Stuve-Wiedemann syndrome, highlights the utility of population-specific databases for variant interpretation. The study suggests that lysosomal storage disorders like Pompe disease and Alpha Mannosidosis, reported in more than six families each, may warrant inclusion in the national newborn screening panel. CTGA serves as a critical resource for clinicians to aid diagnosis and therapeutic decisions, and for public health officials to modify screening strategies. The underrepresentation of Arab populations in global databases (e.g., gnomAD includes only 158 Middle Eastern genomes, 0.2% of its release) emphasizes the importance of databases like CTGA in improving variant annotation and addressing genomic diversity.