English abstract
Consanguinity increases the likelihood of presence of pathogenic mutations in a homo-allelic state. Oman is characterized by high rate of consanguinity which has an adverse outcome by increasing the risk of autosomal recessive conditions. These are the commonest type of diseases in Oman and significantly contribute in increased rate of morbidity and mortality. Identification of the disease-related genes leads immediately to expand knowledge of the functional role of the altered gene and offers better understanding of the physiological basis of the disease phenotype. Autozygosity mapping is a powerful approach that is widely used for detection of autosomal recessive disorders in consanguineous families. This study aimed to uncover the genetic basis of two inherited autosomal recessive conditions in Omani families. Two consanguineous Omani families with different autosomal recessive disorders were enrolled in the study. The first family was characterized by achalasia while the second family has ataxia and epilepsy. Single Nucleotide Polymorphism array has been used to identify the shared autozygous regions between affected individuals. The most promising candidate genes were selected using different filtering approaches related to similarities in functions and pathways. The strongest candidate genes were sequenced and the identified variants were evaluated using in silico mutation prediction tools.
For the family with achalasia, the GUCY1A3 gene, that was recently known to cause achalasia, was considered as the strongest candidate gene. One splice site variant, predicted to affect splicing, was identified. Further evaluations are recommended to confirm its causality by studying its cosegregation with the disorder and its effect on mRNA splicing. For the family with ataxia and epilepsy, the GOSR2 gene showed similar phenotypes to our patients but not identical and thus considered as the promising candidate gene. No causative variant was identified in this gene. The potential next step is to sequence promotor and downstream untranslated regions in GOSR2 and to genotype additional patient that would allow refining the candidate regions.
