The HECT (Homologous to the E6-AP Carboxyl Terminus)-family protein E6AP (E6-associated protein), encoded by the UBE3A gene, is a multifaceted ubiquitin ligase that controls diverse signaling pathways involved in cancer and neurological disorders. The oncogenic role of E6AP in papillomavirus-induced cancers is well known, with its action to trigger p53 degradation in complex with the E6 viral oncoprotein. However, the roles of E6AP in non-viral cancers remain poorly defined. It is well established that loss-of-function alterations of the UBE3A gene cause Angelman syndrome, a severe neurodevelopmental disorder with autosomal dominant inheritance modified by genomic imprinting on chromosome 15q. Moreover, excess dosage of the UBE3A gene markedly increases the penetrance of autism spectrum disorders, suggesting that the expression level of UBE3A must be regulated tightly within a physiologically tolerated range during brain development. In this review, current the knowledge about the substrates of E6AP-mediated ubiquitination and their functions in cancer and neurological disorders is discussed, alongside with the ongoing efforts to pharmacologically modulate this ubiquitin ligase as a promising therapeutic target.

• The diversity of genes and biological pathways involved in AF pathogenesis and variability in individual response to treatment highlights the need for a personalized approach for AF management. Over the past decade, GWAS have identified more than 140 AF-associated loci, and family-based studies have identified rare variants in genes encoding ion channel as well as non–ion channel proteins. • This review discusses studies that have provided novel insights regarding variant-specific pathophysiologic mechanisms that can pave the way for personalized medicine for AF. • Recent translational advances in AF genetics include the development of high-throughput in vitro assays for functional validation of variants of uncertain significance that can bridge the gap in variant classification and risk stratification. • GWAS-derived PRS for AF can be used for predicting AF risk and adverse outcomes. Further studies are needed to validate if AF PRS are superior to traditional risk stratification tools. • Genotype-guided clinical trials and advances in bioengineered preclinical models are needed for developing personalized therapy for AF.

Atrial fibrillation (AF) is a common arrhythmia with a complex genetic basis, yet the molecular mechanisms linking rare and common variants remain unclear. Using induced pluripotent stem cell-derived atrial cardiomyocytes, we uncover a novel mechanism by which a rare pathogenic LMNA variant encoding Lamin A/C disrupts chromatin accessibility and gene regulation at AF-associated loci. Specifically, reduced accessibility at an SCN5A enhancer harboring an AF-associated variant leads to reduced sodium current, conduction abnormalities, and re-entrant AF. These electrophysiological defects are rescued by CRISPR-mediated activation of the SCN5A promoter and enhancer, providing the first molecular evidence of epistatic gene-gene interactions driving arrhythmia risk and mechanistically linking atrial myopathy and AF. At the population level, we demonstrate that carriers of LMNA protein-altering variants with a high polygenic risk score are at a two-fold increased risk of early-onset AF, highlighting the need to integrate rare and common variants for more accurate AF risk assessment.