Clinical exome sequencing (CES) has become an increasingly popular diagnostic tool in patients with heterogeneous genetic disorders, especially in those with neurocognitive phenotypes. Utility of CES in consanguineous populations has not yet been determined on a large scale. A clinical cohort of 149 probands from Qatar with suspected Mendelian, mainly neurocognitive phenotypes, underwent CES from July 2012 to June 2014. Intellectual disability and global developmental delay were the most common clinical presentations but our cohort displayed other phenotypes, such as epilepsy, dysmorphism, microcephaly and other structural brain anomalies and autism. A pathogenic or likely pathogenic mutation, including pathogenic CNVs, was identified in 89 probands for a diagnostic yield of 60%. Consanguinity and positive family history predicted a higher diagnostic yield. In 5% (7/149) of cases, CES implicated novel candidate disease genes (MANF, GJA9, GLG1, COL15A1, SLC35F5, MAGE4, NEUROG1). CES uncovered two coexisting genetic disorders in 4% (6/149) and actionable incidental findings in 2% (3/149) of cases. Average time to diagnosis was reduced from 27 to 5 months. CES, which already has the highest diagnostic yield among all available diagnostic tools in the setting of Mendelian disorders, appears to be particularly helpful diagnostically in the highly consanguineous Middle Eastern population.
Background: Consanguineous marriages are common in the Middle East including the Gulf countries. The rate of consanguinity in Qatar is approximately 54%, which are mainly first cousins' marriages. Previous studies showed that consanguinity increases the prevalence of birth defects and other genetic disorders. Thus, we studied the effects of consanguinity in a cohort of subjects with certain genetic disorders in Qatar. Methods: This cross-sectional study was conducted at two centers in Qatar (Hamad Medical Corporation "HMC" and Shafallah "SC") including 599 Qatari families with certain types of genetic and nongenetic anomalies. Results: Consanguineous marriages were seen in 397 of 599 (66.2%) Qatari families and first cousin group counts for 65% in Qatari population. In the total cohort and at HMC, all consanguineous marriages had a significantly higher risk of Autosomal Recessive disorders than nonconsanguineous marriages (total cohort: odds ratio (OR) = 1.72; 95% CI: 1.10, 2.71; p = .02; HMC: OR = 2.98; 95% CI: 1.37, 6.09; p = .005). On the other hand, at HMC, nonconsanguinity was significantly related to chromosomal abnormality (OR = 6.36; 95% CI: 1.13, 35.85; p = .036). Conclusion: Our data suggest a significant role of parental consanguinity in increasing the prevalence of genetic disorders; mainly Autosomal Recessive disorders.Chromosomal abnormality disorders were significantly higher among nonconsanguineous marriages. These results help better inform policy makers on social, educational, and public health initiatives that might mitigate the impact of genetic disease in the Qatari society. K E Y W O R D S
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