Zerafati-Jahromi et al., 2025 described 14 individuals with HECTD1 variants presenting with a variable neurodevelopmental disorder; nearly half of these individuals carried a diagnosis of autism spectrum disorder (5/11, 45%). This report further demonstrated that conditional knockout of Hectd1 in the neural lineage of mice resulted in microcephaly, severe hippocampal malformations, and complete agenesis of the corpus callosum, while functional studies of selected variants in C. elegans revealed either change-of-function or loss-of-function/haploinsufficient mechanisms, which potentially explains the phenotypic heterogeneity observed in affected humans. Additional de novo variants in HECTD1, including a de novo loss-of-function variant and several de novo missense variants, have previously been identified in ASD probands from the Simons Simplex Collection, the Autism Sequencing Consortium, and the SPARK cohort (Iossifov et al., 2014; Lim et al., 2017; Satterstrom et al., 2020; Zhou et al., 2022), while multiple inherited missense variants with CADD scores > 30 were reported in this gene in Chinese ASD probands from the ACGC cohort (Guo et al., 2018).
Molecular Function
Enables ubiquitin protein ligase activity. Predicted to be involved in positive regulation of proteasomal ubiquitin-dependent protein catabolic process; proteasome-mediated ubiquitin-dependent protein catabolic process; and protein polyubiquitination. Predicted to act upstream of or within several processes, including chordate embryonic development; circulatory system development; and protein ubiquitination.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Sequence variants in HECTD1 result in a variable neurodevelopmental disorder
