Delineating the expanding phenotype of HERC2-related disorders: The impact of biallelic loss of function versus missense variation.

HECT And RLD Domain-Containing E3 Ubiquitin Protein Ligase 2, or HERC2, codes an ubiquitin ligase that has an important role in key cellular processes including cell cycle regulation, DNA repair, mitochondrial functions, and spindle formation during mitosis. While HERC2 Neurodevelopmental Disorder in Old Order Amish is a well characterized human disorder involving HERC2, bi-allelic HERC2 loss of function has only been described in three families and results in a more severe neurodevelopmental disorder. Herein, we delineate the HERC2 loss of function phenotype by describing three previously unreported patients, and by summarizing the molecular and phenotypic information of all known HERC2 missense variants and biallelic loss of function patients. Collectively, these twelve individuals present with recurring features that define a syndrome with varying combinations of severe neurodevelopmental delay, structural brain anomalies, seizures, hypotonia, feeding difficulties, hearing and vision issues, and renal anomalies. This study describes a distinct neurodevelopmental disorder, emphasizing the importance of further characterization of HERC2-related disorders, as well as highlighting the importance of ongoing work into understanding these critical neurodevelopmental pathways.