Gene-based therapeutics for rare genetic neurodevelopmental psychiatric disorders

Abstract

We are in an emerging era of gene-based therapeutics with significant promise for rare genetic disorders. The potential is particularly significant for genetic central nervous system disorders that have begun to achieve Food and Drug Administration approval for select patient populations. This review summarizes the discussions and presentations of the National Institute of Mental Health-sponsored workshop "Gene-Based Therapeutics for Rare Genetic Neurodevelopmental Psychiatric Disorders," which was held in January 2021. Here, we distill the points raised regarding various precision medicine approaches related to neurodevelopmental and psychiatric disorders that may be amenable to gene-based therapies.

Keywords: gene therapy; neurodevelopment; psychiatric disorders.

Graphical abstract

Figure 1

Effect sizes of genetic variation in neurodevelopmental disorders Odds ratios, based on prior findings, are shown in gray, with the width of the line reflecting the range of odds ratios that have been reported for significant variants. Single-nucleotide polymorphisms (SNPs) have very small effect sizes, and some SNPs have been shown to be protective. Rare standing variation can show stronger effect sizes, but as effect sizes increase, such standing variation will be under stronger purifying selection. Ultra-rare variation showing significant association with one or more neurodevelopmental disorders includes copy number variation (CNV), single-nucleotide variation (SNV), and insertions/deletions (indel) and is often de novo or recent within a family, given strong purifying selection.

Figure 2

Proportion of individuals with autism carrying a potentially damaging variant The PAGES epidemiological sample of individuals with autistic disorder was analyzed for rare structural variation (aneuploidies and damaging CNV) and for point mutations (damaging SNV and indels). Potentially damaging variation was identified when structural variation was large or impacted a known genomic disorder region or when point mutations or indels impacted high-confidence autism or developmental delay genes. Cases with a diagnosis of Fragile X syndrome or Down syndrome were also tabulated. Potentially damaging point mutations were more common than potentially damaging structural variation, and the combined yield of potentially damaging variation was substantial at 28%. As more genes for autism are discovered, the yield will likely increase. Adapted from Mahjani et al.