AP2M1. The genetic landscape of neurodevelopmental disorders is shaped as much by what we see as by what we don’t. In 2019, we discovered dominant-negative mutations in AP2M1 as a novel cause of neurodevelopmental disorders with epilepsy, but it also left a lingering question. Judging from large population databases, AP2M1 has all the features of a haploinsufficient gene rather than a dominant-negative disease mechanism. However, protein-truncating variants or deletions in AP2M1 have never been described. In a recent study, we demonstrate that a small deletion on chromosome 3 offers a compelling insight into this mystery. By narrowing down the candidate region of the 3q27.1 deletion syndrome to a 430 kb region, AP2M1 remerges as the most likely candidate. But it also reopens a broader question: Where are the missing haploinsufficient genes?
Tag Archives: mutation intolerance
Constrained coding regions and genetic causes for epilepsy that we might have missed
Genetic architecture. Our reference dataset for genetic variation in humans has become so large that we can increasingly ask the question whether the distribution of genetic variants tells us something about genes and regions within genes without knowing anything about what these genes actually do. For example, it is well established that genes with fewer protein-truncating variants than expected are much more likely to be causative genes for epilepsy and neurodevelopmental disorders than genes that have an average number of these variants. A recent publication in Nature Genetics takes this approach one step further by looking at specific regions within genes rather than entire genes, a somewhat interesting approach that the authors introduce by discussing bullet damage to airplanes in World War II. Continue reading