Abstract:
Human brain development is a complex process involving many cellular pathways. Pathogenic mutations in genes controlling as a whole or in parts, any of these cellular processes result in neurological disorders. It is basically due to defective signaling function in central or peripheral nervous system. The clinical features of such disorders are extremely diverse and overlapping, with even greater genetic heterogeneity. They may either be simple, having Mendelian inheritance or they may be complex. Genetic factors play very important role both in simple and complex neurological diseases. The consequences of such diseases are usually devastating both for affected individuals, their families and society, mainly by affecting the qualities which make human special as person; the character, memory, cognition, communication and skilled movements. In the present study, 11 consanguineous Pakistani families having neurological disorders of Mendelian inheritance were investigated using next generation sequencing (NGS) technologies. Rare and disease causing variants mostly occur in coding part of genome. Whole exome sequencing (WES) was used as a method of choice in the current study because of the heterogeneous nature of neurological disorders both clinically and genetically. Variants obtained from WES were prioritized based on their inheritance pattern, disease association, functional relevance and pathogenicity score as predicted by different bioinformatics tools such as Mutation Taster and PolyPhen-2. Segregation of all the variants were confirmed using Sanger sequencing. Ten novel and one already reported mutation were identified in this study. At present there are no effective treatment strategies available for most of these diseases. Therefore, identification of gene/s and pathogenic variant/s in these diseases will help understand underlying molecular mechanisms better, and lead to improved strategies both for genetic counseling and potential therapeutics
