De novo missense variants in TRIM28 identified in individuals with neurodevelopmental delay show features of transposable element activation

TRIM28 is an epigenetic co-repressor protein that silences transposable elements (TEs). Although loss-of-function studies in mice led to neurodevelopmental defects, a functional link between TRIM28 and human neurodevelopment has yet to be established. In this study, we describe two patients with neurodevelopmental delay who carry de novo TRIM28 missense variants. Using CRISPR-edited induced pluripotent stem cell lines and differentiated neural organoids, we demonstrate that these variants result in the loss of the histone mark H3K9me3 over TEs. This releases the regulatory potential of TEs resulting in altered expression of nearby genes. These findings could be replicated using CRISPRi-based TRIM28 silencing, which suggests that the two variants result in a loss of function. Our results highlight the critical role of TRIM28 in regulating TEs during human brain development, establishing a link between TRIM28 variants and neurodevelopmental delay.