Reaching the full potential of precision medicine depends on the quality of personalized genome interpretation. In order to facilitate precision medicine in regions of the Middle East and North Africa (MENA), a population-specific genome for the indigenous Arab population of Qatar (QTRG) was constructed by incorporating allele frequency data from sequencing of 1,161 Qataris, representing 0.4% of the population. A total of 20.9 million single nucleotide polymorphisms (SNPs) and 3.1 million indels were observed in Qatar, including an average of 1.79% novel variants per individual genome. Replacement of the GRCh37 standard reference with QTRG in a best practices genome analysis workflow resulted in an average of 7* deeper coverage depth (an improvement of 23%) and 756,671 fewer variants on average, a reduction of 16% that is attributed to common Qatari alleles being present in QTRG. The benefit for using QTRG varies across ancestries, a factor that should be taken into consideration when selecting an appropriate reference for analysis.

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Exome sequencing of families of related individuals has been highly successful in identifying genetic polymorphisms responsible for Mendelian disorders. Here, we demonstrate the value of the reverse approach, where we use exome sequencing of a sample of unrelated individuals to analyze allele frequencies of known causal mutations for Mendelian diseases. We sequenced the exomes of 100 individuals representing the three major genetic subgroups of the Qatari population (Q1 Bedouin, Q2 Persian-South Asian, Q3 African) and identified 37 variants in 33 genes with effects on 36 clinically significant Mendelian diseases. These include variants not present in 1000 Genomes and variants at high frequency when compared to 1000 Genomes populations. Several of these Mendelian variants were only segregating in one Qatari subpopulation, where the observed subpopulation specificity trends were confirmed in an independent population of 386 Qataris. Pre-marital genetic screening in Qatar tests for only 4 out of the 37, such that this study provides a set of Mendelian disease variants with potential impact on the epidemiological profile of the population that could be incorporated into the testing program if further experimental and clinical characterization confirms high penetrance.

BackgroundThe prevalence of type 2 diabetes (T2D) is increasing in the Middle East. However, the genetic risk factors for T2D in the Middle Eastern populations are not known, as the majority of studies of genetic risk for T2D are in Europeans and Asians.MethodsAll subjects were ≥3 generation Qataris. Cases with T2D (n = 1,124) and controls (n = 590) were randomly recruited and assigned to the 3 known Qatari genetic subpopulations [Bedouin (Q1), Persian/South Asian (Q2) and African (Q3)]. Subjects underwent genotyping for 37 single nucleotide polymorphisms (SNPs) in 29 genes known to be associated with T2D in Europeans and/or Asian populations, and an additional 27 tag SNPs related to these susceptibility loci. Pre-study power analysis suggested that with the known incidence of T2D in adult Qataris (22%), the study population size would be sufficient to detect significant differences if the SNPs were risk factors among Qataris, assuming that the odds ratio (OR) for T2D SNPs in Qatari’s is greater than or equal to the SNP with highest known OR in other populations.ResultsHaplotype analysis demonstrated that Qatari haplotypes in the region of known T2D risk alleles in Q1 and Q2 genetic subpopulations were similar to European haplotypes. After Benjamini-Hochberg adjustment for multiple testing, only two SNPs (rs7903146 and rs4506565), both associated with transcription factor 7-like 2 (TCF7L2), achieved statistical significance in the whole study population. When T2D subjects and control subjects were assigned to the known 3 Qatari subpopulations, and analyzed individually and with the Q1 and Q2 genetic subpopulations combined, one of these SNPs (rs4506565) was also significant in the admixed group. No other SNPs associated with T2D in all Qataris or individual genetic subpopulations.ConclusionsWith the caveats of the power analysis, the European/Asian T2D SNPs do not contribute significantly to the high prevalence of T2D in the Qatari population, suggesting that the genetic risks for T2D are likely different in Qataris compared to Europeans and Asians.

BackgroundClinical exome sequencing (CES) is rapidly becoming the diagnostic test of choice in patients with suspected Mendelian diseases especially those that are heterogeneous in etiology and clinical presentation. Reporting large CES series can inform guidelines on best practices for test utilization, and improves accuracy of variant interpretation through clinically‐oriented data sharing.MethodsThis is a retrospective series of 509 probands from Qatar who underwent singleton or trio CES either as a reflex or naïve (first‐tier) test from April 2014 to December 2016 for various clinical indications.ResultsThe CES diagnostic yield for the overall cohort was 48.3% (n = 246). Dual molecular diagnoses were observed in 2.1% of cases; nearly all of whom (91%) were consanguineous. We report compelling variants in 11 genes with no established Mendelian phenotypes. Unlike reflex‐WES, naïve WES was associated with a significantly shorter diagnostic time (3 months vs. 18 months, p < 0.0001).ConclusionMiddle Eastern patients tend to have a higher yield from CES than outbred populations, which has important implications in test choice especially early in the diagnostic process. The relatively high diagnostic rate is likely related to the predominance of recessive diagnoses (60%) since consanguinity and positive family history were strong predictors of a positive CES.

Prompted by cases of acute hepatitis in expatriate workers presenting at Alkhor Hospital, Qatar, a limited prospective observational study was conducted from July 2005 to June 2006 to determine the epidemiological and clinical features of patients (predominantly Nepalese) presenting with acute hepatitis. Countrywide during that period samples from 86 Nepalese presenting at different centers were found to be anti-HEV IgG positive and 50 of these were also positive for anti-HEV IgM. Fifty-eight of those Nepalese were seen and treated at Alkhor Hospital and of them 43 were confirmed as cases of acute HEV, being positive for both anti-HEV IgM and IgG. The remaining 15 were diagnosed as probable cases of acute HEV on the basis of clinical and epidemiological similarity. It seems likely that transit in Kathmandu in reportedly unsanitary conditions was the focus of infection. In some of those examined at Alkhor, ultrasound detected a thickened gallbladder wall in 30 of 39 (76.9%) with two cases having clinical acalcular cholecystitis. Higher levels of alanine aminotransferase and aspartate aminotransferase were associated with severe disease and derangement in coagulation. On the available evidence hepatitis E was imported by expatriate workers and it is clear that medical screening of these workers pre- and post-arrival must be improved to prevent further outbreaks. It is also essential that health care workers in Qatar are made aware of this ongoing problem of imported HEV and understand the variable presentation of the condition.

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We investigated the incidence of hepatitis B (HBV) and C (HCV) virus infection among patients with liver disease in Qatar from 2000 to 2005. The grading and staging of HBV and HCV cases were obtained from pathology reports at the principal reference laboratory for Qatar. Of the 915 liver patients studied, 29.4% had HCV and 2.5% had HBV. The incidence of HBV and HCV infection was greater in non-Qataris than Qatari nationals and in males than females, especially for HCV. Most cases were uncomplicated (89.0%) and had no inflammation (76.4%). The incidence of HCV has been increasing in liver patients in recent years up to a rate of 481 per 1000 patients with liver disease in 2005. Hepatitis B and C viral infections in