Background: Whole exome sequencing (WES), which focuses on sequencing of protein-coding regions of human genome, has greatly improved the identification of causal mutations for diverse human genetic disorders in the past four years. We applied WES as a molecular diagnostic tool to identify disease-causing mutations in consanguineous families displaying autosomal recessive (AR) disorders in Qatar. AR diseases are usually severe and rare that occurs with higher rate in consanguineous families. In Qatar, like other Middle East countries, consanguineous marriage and endogamy are common (54%) that results in a higher incidence of several/new AR disorders where many of these disorders are yet to be defined and their causative genes are to be discovered. In order to decrease the overall socio-economic burden of such diseases in the society and development of specific testing tools that will be helpful with the molecular diagnosis, parental testing, carrier identification, and informed genetic counseling, we must first discover the causative genes of these recessive disorders. Methods: All of the experimental (whole exome library preparation, capturing and sequencing) and bioinformatics analyses were performed according to our well-established protocols at Genome Quebec Innovation Center, Montreal, Canada. Results: We performed WES on several consanguineous families, with one or more affected children, where the result of initial molecular screening of known or potential candidate genes was negative. Because of unaffected status of parents and their consanguinity, the mode of inheritance was considered to be autosomal recessive. We also tested de novo and X-linked mode of inheritance in families with one or only male affected child. Based on these assumptions, we identified the definitive damaging mutations for Hypophosphatemic rickets; Hurler syndrome; Glycogen storage disease; Dubowitz-like syndrome; Seckel syndrome; Geleophysic dysplasia; Limb-girdle muscular dystrophy; Multiple Fractures; Metachromatic Leukodystrophy; Immunodeficiency and Juvenile onset cataract. In addition, several candidate genes were identified in families with mental retardation (n=3); CNS anomaly (n=1); eye anomalies (n= 26); peripheral neuropathy (n=7); axonal peripheral neuropathy (n=3) and oro-facio-digital syndrome (n=2), that have been considered for functional follow-up investigations and further characterizations. Conclusion: Our study highlights the importance of using WES as molecular diagnostic approach for discovery pathogenic gene mutations compared to traditional molecular genetic testing. We showed that the WES was successful to identify causal mutations underlying phenotypically complex disorders in ~46% of our patients. The results of this study will help to establish population-specific diagnostic panels, and improve clinical diagnosis and patient management in the country.


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