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.

Association of Genetic Variants with Colorectal Cancer in the Extended MENA Region: A Systematic Review.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide and the third leading cause of cancer-related death. It is a heterogeneous disease that develops through different genetic and epigenetic mechanisms. To date, no comprehensive systematic review investigating genetic risk factors for familial and sporadic CRC has been performed on the extended MENA (eMENA) region. AIMS: This study aimed to systematically analyze genetic variations significantly associated with CRC in the eMENA region. METHODS: We searched four literature databases (PubMed, Scopus, Science Direct, and Web of Science) from the time of inception until May 2019 using broad search terms to obtain all reported genetic data related to eMENA patients with CRC. Variants with an OR>1 that are associated with CRC were identified. RESULTS: A total of 1,200 studies were obtained from our search method, 27 of which met the inclusion criteria for our systematic review, with a total of 8,230 CRC patients and 7,611 controls. Of these, 1,941 patients distributed throughout nine eMENA countries were found to carry 46 variants in 33 different genes. Interestingly, 19 variants were unique to CRC patients in the eMENA region. INTERPRETATION: This is the first systematic review to capture the spectrum of variants significantly associated with CRC in the eMENA region. There appears to be a distinctive clinical picture for eMENA patients with CRC, and the range and distribution of variants among patients from the eMENA region differ from those noted in other ethnic groups.

Genetic Epidemiology of Glucose-6-Phosphate Dehydrogenase Deficiency in the Arab World.

A systematic search was implemented using four literature databases (PubMed, Embase, Science Direct and Web of Science) to capture all the causative mutations of Glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDD) in the 22 Arab countries. Our search yielded 43 studies that captured 33 mutations (23 missense, one silent, two deletions, and seven intronic mutations), in 3,430 Arab patients with G6PDD. The 23 missense mutations were then subjected to phenotypic classification using in silico prediction tools, which were compared to the WHO pathogenicity scale as a reference. These in silico tools were tested for their predicting efficiency using rigorous statistical analyses. Of the 23 missense mutations, p.S188F, p.I48T, p.N126D, and p.V68M, were identified as the most common mutations among Arab populations, but were not unique to the Arab world, interestingly, our search strategy found four other mutations (p.N135T, p.S179N, p.R246L, and p.Q307P) that are unique to Arabs. These mutations were exposed to structural analysis and molecular dynamics simulation analysis (MDSA), which predicting these mutant forms as potentially affect the enzyme function. The combination of the MDSA, structural analysis, and in silico predictions and statistical tools we used will provide a platform for future prediction accuracy for the pathogenicity of genetic mutations.