Delineating the clinical and molecular spectrum of the neurodevelopmental disorder associated with SET

SET is a member of the inhibitor of histone acetyltransferases complex involved in transcriptional silencing and gene regulation. Pathogenic variants in SET are postulated to cause neurodevelopmental disorder (NDD) phenotypes, but as only a few individuals are described, detailed clinical information is scarce. Hence, currently, counseling on phenotypes and prognosis of this condition remains challenging.

Here, we describe the clinical phenotype and mutational spectrum of 23 unreported individuals harboring (likely) pathogenic variants in SET.

Phenotypes include global developmental delay, often with pronounced hypotonia, delayed motor development, and speech and language delay, ultimately evolving into (mild) intellectual disability. Comorbidities include behavioral concerns, sleep disturbances, and variable nonspecific ocular problems. Next-generation computer-assisted phenotyping using GestaltMatcher showed limited overlapping facial features between affected individuals and differences compared with disorders caused by related chromatin-modifying genes in individuals. In addition, we generated a DNA methylation signature able to distinguish individuals carrying pathogenic variants in SET from individuals with other neurodevelopmental disorders and healthy controls. We used this DNA methylation signature to assess the pathogenicity of 2 variants of uncertain clinical significance in SET found in 2 additional individuals.

Together, this expands the knowledge on SET-related disorders and provides novel approaches for their diagnosis.