Success stories in genomic medicine from resource-limited countries.

In recent years, the translation of genomic discoveries into mainstream medical practice and public health has gained momentum, facilitated by the advent of new technologies. However, there are often major discrepancies in the pace of implementation of genomic medicine between developed and developing/resource-limited countries. The main reason does not only lie in the limitation of resources but also in the slow pace of adoption of the new findings and the poor understanding of the potential that this new discipline offers to rationalize medical diagnosis and treatment. Here, we present and critically discuss examples from the successful implementation of genomic medicine in resource-limited countries, focusing on pharmacogenomics, genome informatics, and public health genomics, emphasizing in the latter case genomic education, stakeholder analysis, and economics in pharmacogenomics. These examples can be considered as model cases and be readily replicated for the wide implementation of pharmacogenomics and genomic medicine in other resource-limited environments.

VKORC1 variants as significant predictors of warfarin dose in Emiratis.

Purpose: Variability in response to warfarin is one of the main obstacles challenging its use in clinical practice. Vitamin K epoxide reductase complex (VKORC) is the target enzyme of warfarin, and variations in the form of single nucleotide polymorphisms (SNPs) in VKORC1, coding for this enzyme, are known to cause resistance to warfarin treatment. This study aimed to explore VKORC1 variants in Emirati patients receiving warfarin treatment and to correlate their genotypes at the studied SNPs to their maintenance warfarin dose. Patients and methods: Sanger sequencing of the majority of the VKORC1 gene was applied to samples from 90 patients and 117 normal individuals recruited from Tawam Hospital, Al-Ain, UAE. Genotypes at the following variants were determined (rs9923231, rs188009042, rs61742245, rs17708472, rs9934438, rs8050894, rs2359612, rs7294). Statistical analysis was applied, including ANOVA, cross-tabulation, and multiple linear regression analysis, to determine the ability of nongenetic factors (age and gender) and genetic factors (VKORC1 genotypes) to explain variability in warfarin dose in patients. Results: Different frequencies of minor alleles were detected in the selected SNPs. Significant variation among genotypes at six VKORC1 variants were identified (rs9923231, rs9934438, rs8050894, rs2359612, rs7294). The main predictors for warfarin dose were rs9923231, age, and rs61742245 with 50.7% of the average warfarin dose in our sample could be explained by a regression model built on these three factors. Conclusion: This is the first report of the explanatory power of VKORC1 genotypes and nongenetic factors (age and gender) on warfarin dose among Emiratis. Also, this study highlighted the positive effect of considering rare pharmacogenomic variants on explaining warfarin dose variability.

Clinical and molecular analysis of a novel COLQ missense mutation causing congenital myasthenic syndrome in a Syrian family.

BACKGROUND: Congenital myasthenic syndromes with end-plate acetylcholinesterase deficiency are rare autosomal recessive disorders characterized by onset of the disease in early childhood, general weakness exacerbated by exertion, ophthalmoplegia, and refractoriness to anticholinesterase drugs. To date, all reported cases have been attributed to mutations in 18 genes including the COLQ gene that encodes a specific collagen that anchors acetylcholinesterase at the basal lamina of the neuromuscular junction. We identified a Syrian family with two children of consanguineous parents from two branches affected with congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency. METHOD: The absence of acetylcholinesterase antibodies was demonstrated biochemically. Consequently, all the coding regions, exon-intron boundaries, and the 5' and 3' untranslated regions of the COLQ gene were amplified and sequenced using the Sanger sequencing method. RESULTS: We observed that the severity of the phenotype in the two affected children differed. One child had mild symptoms that included difficulties in gait and feeding with mild respiratory insufficiency. Her sibling died in the first months of life because of severe respiratory failure. The second patient had severe symptoms from birth and has been mechanically ventilated. DNA sequencing revealed a novel homozygous single nucleotide substitution mutation (c.1010T>C) in the COLQ gene in both patients. This substitution leads to a missense amino acid substitution at position 337 of the protein (p.Ile337Thr). This mutation is likely to impair ColQ's trimeric organization and therefore its anchoring within the synaptic basal lamina. CONCLUSION: We identified the molecular cause underlying congenital myasthenic syndrome in two patients. The marked phenotypic variation suggests that other factors including modifier genes may affect the severity of this disease.