The HGG Advances Award for Outstanding Early Career Publication recognizes research excellence from ASHG members who have recently begun their independent research careers. Philip Boone, a clinical geneticist, former postdoc, and now an Instructor in the lab, was awarded this for his paper on SMC3 mutations in HGG Advances at the 2024 ASHG conference in Denver, CO. Congratulations, Philip!
Here is a summary of the paper:
Missense and indel variants in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), featuring intellectual disability, growth deficiency, and dysmorphism. Despite marked mutational constraint in the population, the phenotypes and traits associated with SMC3 loss-of-function (LoF) variants have not been previously reported, and variable phenotypes, including developmental lethality, have been proposed. We delineated the clinical characteristics of SMC3 LoF variant carriers, unexpectedly identifying mild and incompletely penetrant features reminiscent of CdLS but considerably attenuated. Expression and epigenetic data from SMC3 LoF models exhibited similarly incomplete overlap with those of CdLS, further supporting allelism at this locus with missense variants acting as dominant-negative alleles conveying more severe effects. In summary, this study identified a novel disease association for a core component of the cohesin complex and provides an example of a framework for delineating additional ‘missing’ phenotypes attributable to loss-of-function-constrained genes. This work had an immediate clinical impact, as the clinical interpretation of SMC3 LoF variants identified via a commercially available prenatal screening method was updated to reflect our findings. Furthermore, it set the stage for Philip’s ongoing studies to create innovative in vitro models of known and novel cohesinopathies.