Identifying Genetic causes of Autosomal Recessive Intellectual Disability

Intellectual disability (ID) is a limitation in intellectual functioning and adaptive behavior. Genetic etiologies play a major role in ID, and its prevalence is estimated to be three times more in countries known for consanguineous marriages. The practice of consanguineous marriage has been the culturally preferred in Oman and estimated to be 50-55% of marriages, among which the majority are first cousin marriages. This increases the incidence of autosomal recessive disorders that have both a social and an economical impact on the nation. Genetic counseling is practiced nationwide to educate families and estimates risks, and aiming prevention of genetic disorders. Proper clinical diagnosis with mutational confirmatory analysis provides a proper genetic counseling. The contribution of recessive mutations to ID is as high as 25% of genetic causes. Thus far, only minority of these autosomal recessive genes have been identified. However, next generation sequencing technologies made gene discovery more achievable and rapid. Whole exome sequencing (WES) is defined as sequencing the exons of all known protein-coding genes. When WES is combined with homozygosity mapping, it has the added benefit of being able to offer a rapid method for screening for candidate disease-causing mutations. The aims of this study are, first, to create a database of detailed phenotypes of affected families. This will assist in identifying new syndromes or further delineating and characterizing known phenotypes. Second, to establish a rapid method of identifying candidate mutations by using WES on one or more affected individuals within a family. Third, perform gene ex pression and function studies according to the identified mutations to provide additional evidence for causation. The benefits of this study will be evident at multiple levels. The research will enable the identification of new genes that will further enlighten understanding of biological mechanisms and the pathology of diseases leading to improved clinical management and therapies. In addition to specific novel gene identification, WES will provide more information about genomic variants in Oman, promoting future molecular diagnostics, carrier screening, prevention, and risk assessment. This study will continue previous efforts to develop local expertise, bioinformatics and resources for genomics scientists and physicians in Oman.