Grant: Project Grant

The program goals are to identify new genes for intellectual disability (ID), focusing mainly on autosomal recessive (AR) causes, to deduce their functions, to direct findings back to the clinic, and to identify therapeutic opportunities. The vast majority with ID currently receive no molecular diagnosis-a shortcoming that significantly impacts health and lifespan. Knowing the causative gene benefits through diagnosis, care and treatment, overall health and lifespan, and counselling and planning for families. AR forms of ID are believed to account for a large proportion of affected individuals, and are the main genetic cause of ID in countries where within-family marriage (consanguinity) is common. However, attempts to map the genes responsible have been poorly explored. Mapping genes for autosomal recessive disorders can be performed with great efficiency in consanguineous families with multiple affected individuals (MPX) using microarray genotyping combined with next generation DNA sequencing approaches. We have completed studies of 192 MPX consanguineous non-syndromic ID families and identified 38 new genes. We aim to continue with >300 additional MPX, and >100 single affected (SPX) families (or proband/mother/father trios) from countries where consanguinity is common. We aim to identify causative genes/mutations in these families, using a combination of genotyping and next generation sequencing. Genes identified in consanguineous families are also relevant to outbred populations, thus we plan to survey the genes identified in >2500 ID patients from Canada. Our studies to date have already had an impact on diagnosis, and the proposed work will add significantly to this legacy. The results will also help illuminate the pathophysiology, facilitating the development of treatments. Understanding the genetics of these diseases will improve diagnosis and treatment in the long term.