A large number of susceptibility genes for autism and schizophrenia have been identified, although the function of many of these risk factors in regulating neuronal development is not well understood. Copy number variations (CNVs), structural rearrangements of the genome in which entire chromosomal regions may be either deleted or duplicated, produce variability in the expression level of affected genes.

CNVs in the 15q11.2 chromosomal region have emerged as prominent risk factors for various neuropsychiatric disorders, including autism, schizophrenia and intellectual disability. Microduplications of 15q11.2 have been associated with autism, whereas microdeletions have been identified as one of the three most frequent CNV risk factors for schizophrenia. Recent studies have established 15q11.2 CNVs as prominent dosage-dependent genetic disease risk factors for neuropsychiatric disorders¹.

Hongjun Song and his team at Johns Hopkins University in Baltimore plan to investigate the biological role of these CNVs in neural development using human neurons derived from induced pluripotent stem (iPS) cells. iPS cells reprogrammed from human somatic cells — cells that form the body — offer an opportunity to recapitulate both normal and pathologic human tissue development in defined conditions, thereby providing a new way to understand human disorders and facilitate drug development.

Song and his team have generated a collection of well-characterized iPS cell lines with different genotypes, including 15q11.2 deletions, 15q11.2 duplications and controls. Early results suggest that CYFIP1, one of the four genes encoded by this region, plays a key role in the growth and structural organization of neural precursors for the human cortex. The researchers aim to use a combination of human cell culture assays, in vivo transplantation studies and animal models to determine how variation in gene copy number within the 15q11.2 CNV alters cellular function and contributes to risk for psychiatric disorders.