Current studies are geared towards identifying genetic risk variants for neurodevelopmental disorders such as autism, intellectual disability, and schizophrenia. However, these analyses are complicated by extensive genetic heterogeneity. Oftentimes, more than one gene or genomic region are implicated for a specific neurodevelopmental disorder, for example, there are more than half a dozen genomic regions implicated in autism. And, even among the individuals carrying the same genetic variant, significant variability in clinical presentation has been documented. These variants are also seen in unaffected or mildly affected parents complicating diagnosis, management and risk counseling in these families. This proposal is aimed at solving one such rare variant genome that occurs at an estimated frequency of 1 in 2,000 in the general population. This variant is a 520 kilobases of genomic deletion removing about 6 genes from chromosomal region 16p12.1. This variant was initially identified in children with severe developmental delay and intellectual disability. However, further studies on parents showed that about 95% of these deletions were transmitted from a parent. Upon further clinical testing, it was found that carrier parents were more at risk of manifesting neuropsychiatric features compared to non-carrier parents. Interestingly, it was also found that about 25% of the affected children with the deletion also carried another large but rare deletion or duplication elsewhere in the genome. These children with two hits were more severely affected than those with one hit. This suggested that, while 16p12.1 deletion, by itself, can lead to neuropsychiatric features as in parents), in concert with additional rare variants at another location in the genome, could result in a more severe clinical feature as in the affected child). We propose to recruit about 20 families for complete clinical and genomic analysis. This will enable to completely understand how different variants in combination with 16p12.1 deletion can lead to distinct neurodevelopmental phenotypes. We have developed novel algorithms to find specific combinations of variants towards disease risk compared to random chance or to the general population. We believe that our proposal will help dissect a substantial part of genetics of these disorders using 16p12.1 as an anchor.