PROJECT SUMMARY/ABSTRACT Intellectual disability (ID) affects 1-3% of the world population. Six and a half million Americans have been diagnosed with ID. Identification of genes and variants that cause ID in a variety of populations. i.e., African, Asian, and European is highly beneficial for understanding brain mechanism and function, development of treatment modalities, and diagnosis through genetic screening. Although >1000 genes have been identified for ID, most genes remain to be uncovered. For this study we will ascertain 500 ID families from Finland, Hungary (Romani and Magyar), Mali, and Pakistan. Families with ID due to a FMR1 repeat expansion (Fragile X syndrome) or environmental exposures (trauma or infection) will be excluded. The studied will consist of trios (affected proband and parents), nuclear and extended families including those with consanguinity. Next-generation sequencing will be performed on DNA samples obtained from the proband and his/her parents for the trios and on average three affected members for the nuclear/extended families. Analysis of the sequence data will be performed by implementing tools developed in house that are incorporated in Jupyter Notebooks using information on variant frequency, deleterious status, and conservation as well as database annotations on clinical etiology, animal models, and brain expression. Candidate variants will be validated and for nuclear/extended families tested for segregation with ID using DNA samples obtained from all available family members. Three-dimensional protein modeling will be performed to investigate how identified variants affect protein function. Once a putatively causal ID variant is identified, we will screen our collection of ID pedigrees and use GeneMatcher to find additional ID families that segregate potentially pathogenic variants within the same gene. For newly identified ID genes, spatiotemporal expression profiling will be performed in the developing and adult brain and nervous system to provide additional evidence of the gene’s involvement in ID etiology and to better understand how disruption of the gene can impact brain function. ID has been understudied in African populations. The study of West Africans (Mali) should bring about new knowledge which can directly impact African Americans since their ancestors were brought to the Americas from West Africa through the trans-Atlantic slave trade. Pakistani families due to their size and structure are highly beneficial in identify ID genes. The Hungarian Romani and the Finnish both belong to founder populations which can aid in variant identification. This unique resource of families from Africa, Asia, and Europe will aid in better understanding of the genetic etiology of ID and the role genetic plays in brain function. The new knowledge obtained from this study should be beneficial to the health of minority and non-minority American populations.