Language

English

Publication Date

3-6-2025

Journal

American Journal of Human Genetics

DOI

10.1016/j.ajhg.2025.01.001

PMID

39879987

PMCID

PMC11947180

PubMedCentral® Posted Date

1-28-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Dysregulation of genes encoding the homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases has been linked to cancer and structural birth defects. One member of this family, the HECT-domain-containing protein 1 (HECTD1), mediates developmental pathways, including cell signaling, gene expression, and embryogenesis. Through GeneMatcher, we identified 14 unrelated individuals with 15 different variants in HECTD1 (10 missense, 3 frameshift, 1 nonsense, and 1 splicing variant) with neurodevelopmental disorders (NDDs), including autism, attention-deficit/hyperactivity disorder, and epilepsy. Of these 15 HECTD1 variants, 10 occurred de novo, 3 had unknown inheritance, and 2 were compound heterozygous. While all individuals in this cohort displayed NDDs, no genotype-phenotype correlation was apparent. Conditional knockout of Hectd1 in the neural lineage in mice resulted in microcephaly, severe hippocampal malformations, and complete agenesis of the corpus callosum, supporting a role for Hectd1 in embryonic brain development. Functional studies of select variants in C. elegans revealed dominant effects, including either change-of-function or loss-of-function/haploinsufficient mechanisms, which may explain phenotypic heterogeneity. Significant enrichment of de novo variants in HECTD1 was also shown in an independent cohort of 53,305 published trios with NDDs or congenital heart disease. Thus, our clinical and functional data support a critical requirement of HECTD1 for human brain development.

Keywords

Humans, Animals, Neurodevelopmental Disorders, Mice, Ubiquitin-Protein Ligases, Male, Female, Child, Caenorhabditis elegans, Mice, Knockout, Child, Preschool, Adolescent, Phenotype, Epilepsy, Mutation, Attention Deficit Disorder with Hyperactivity, Autistic Disorder, HECTD1, ubiquitin-proteasome system, neurodevelopmental disorders, epilepsy, autism

Published Open-Access

yes

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