Genome-wide association studies and whole-genome sequencing have uncovered many variants that increase susceptibility to neurodevelopmental disorders. Frequently, the causal variants within an associated locus are unknown because common risk variants are located within large haplotype blocks spanning extensive stretches of the noncoding genome. Similar to how the impact of rare noncoding risk variants identified by whole genome sequencing on molecular traits is typically unknown without functional assays. Through the use of high-throughput sequencing and barcode technology, thousands of regulatory elements can be functionally validated at once in a massively parallel reporter assay (MPRA). The effects of genetic variants in cis- and trans-regulatory elements, as well as posttranscriptional processes, on gene regulation can be evaluated using MPRA, which has been adapted to several experimental designs. This article aims to provide a comprehensive overview of the various MPRA designs that have been used or that may be used in the future to validate genetic variants associated with neurodevelopmental disorders experimentally. Although MPRA has limitations, such as not modeling genomic context, this assay can aid in narrowing down the underlying genetic causes of neurodevelopmental disorders by screening thousands of sequences in a single experiment. Finally, researchers discuss potential future uses of MPRA, including studies of gene-by-environment interactions and pharmacogenetics.
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