Accelerated Discovery of Molecules and Biological Pathways Perturbed in Mendelian Neurological Diseases

The development of the human central nervous system involves a complex and precisely controlled cascade of molecular and cellular events. Even minor abnormalities in these processes can result in subtle defects that have devastating implications for brain function, or predispose an individual to later onset neurodegenerative disease. Genetic studies of inherited brain abnormalities and neurodegenerative diseases have provided a proven and valuable way to discover molecules which are involved in normal human brain development and function. However these studies are often hampered by the availability of only small families with these conditions, which have not previously been considered appropriate for new disease gene discovery. Recently a few research groups have shown that cutting edge genetic technologies may be used to investigate smaller families to expedite disease gene discovery. However despite these recent discoveries comparatively little remains known about the intricate molecular processes that orchestrate brain development or that underlie neurodegenerative disease. Consequently further neurological disease gene discovery is desperately required.


The Centre for Community Genomic Studies (CCGS) is a recently formed international consortium for the investigation of inherited diseases which occur amongst consanguineous communities (in the UK, Oman, Iran, Malaysia, India, and the Amish; USA). A main aim of the consortium is the translation of research findings into scientific and community benefit, and a number of our previous discoveries have enabled us to establish potentially lifesaving diagnostic testing programs. Through this consortium we have identified substantial numbers of families with forms of inherited neurological disease. In this proposal we aim to apply new sequencing technologies to discover the genes and mutations responsible for 10 neurological conditions for which we have already mapped the chromosomal location of the disease gene. We also aim to analyse 20 ?smaller? families with individuals with inherited forms of developmental delay to demonstrate the efficiency of this approach to accelerate gene discovery. Consequently by applying modern genomic technologies to hasten the identification of genes responsible for a range of neurological conditions made accessible through the CCGS, this initiative offers considerable potential to increase our knowledge of a range of neurological disorders, as well as provide more effective local diagnostic, counselling and educational programs to the communities involved in the project.

Genomic studies of inherited brain malformations and neurodegenerative diseases have provided invaluable insights into molecules and biological pathways involved in human brain development and function. To circumvent limitations imposed by locus heterogeneity and diagnostic misclassifications, these studies have typically involved the investigation of large families with multiple affected individuals. However despite these molecular discoveries comparatively little remains known about the intricate molecular processes that orchestrate brain development, or that underlie neurodegenerative disease, and the identification of further neurological disease genes is desperately required. Recently, avant-garde genetic studies have indicated the potential for whole-exome re-sequencing of smaller families, involving just 2-3 affected cases, to identify novel disease genes. This approach offers great promise for the accelerated discovery of normal and pathological neurobiological processes.

The Centre for Community Genomic Studies (CCGS) is a recently formed international consortium for the investigation of inherited diseases which occur amongst consanguineous communities (UK, Oman, Iran, Malaysia, India, and Amish) and the translation of research findings into scientific and community benefit. Through this consortium we have access to substantial numbers of families with forms of inherited neurological disease. By identifying and studying large patient groups of particular diseases which occur at high frequency in these communities we have been able to robustly position novel gene loci responsible for four neurodevelopmental conditions, as well as six forms of neurodegenerative disease. We have also identified large numbers of smaller consanguineous families with at least two or three individuals affected by variable degrees of developmental delay either in isolation, or involving other clinical features. In this proposal we aim to apply new sequencing technologies to discover the genes and mutations responsible for each of the 10 conditions which we have already mapped. In parallel with this we intend to undertake whole exome analysis in 20 smaller families with forms of neurological disease and demonstrate the efficacy of this approach to streamline gene discovery. By applying modern genomic technologies to accelerate the identification of genes responsible for a range of neurological conditions made accessible through the CCGS community genetics programs, this initiative offers considerable potential to increase our knowledgebase of both neurodevelopmental and neurodegenerative pathways.