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The homologous to E6AP C-terminus (HECT) E3 ubiquitin ligase family member HECTD1 is essential for embryonic brain development. HECTD1 mediates key developmental pathways including cell signaling, gene expression, and neural lineage formation. Dysregulation of HECTD1 has been linked to neurodevelopmental abnormalities ranging from autism to epilepsy. Recent clinical studies have delineated a variable neurodevelopmental disorder associated with HECTD1 sequence variants (PMID:39879987).
Through an international GeneMatcher effort, 14 unrelated individuals with 15 distinct HECTD1 variants were identified presenting with neurodevelopmental disorder, including autism spectrum disorder, attention-deficit/hyperactivity disorder, and epilepsy (PMID:39879987). The variant spectrum comprised 10 missense changes, 3 frameshift, 1 nonsense, and 1 canonical splice-site variant. Ten variants occurred de novo, two were inherited as compound heterozygous alleles, and three had unknown inheritance. No clear genotype–phenotype correlation was apparent across this cohort.
Significant enrichment of de novo HECTD1 variants was confirmed in an independent analysis of 53,305 published trios with neurodevelopmental disorders and congenital heart disease, supporting a primary role for heterozygous loss-of-function and change-of-function alleles (PMID:39879987). The consistent observation of de novo heterozygous variants fulfills key ClinGen genetic evidence criteria for dominant disorders. Formal segregation data across multiple families remain limited but suggest recurrence of pathogenic alleles.
Functional assessment in a conditional neural-lineage knockout mouse model of Hectd1 recapitulated core human phenotypes, including microcephaly, severe hippocampal malformations, and complete agenesis of the corpus callosum, supporting haploinsufficiency as the predominant pathogenic mechanism (PMID:39879987).
Complementary in vivo studies in Caenorhabditis elegans expressing select human HECTD1 variants revealed dominant effects, with some alleles exhibiting change-of-function and others showing loss-of-function or haploinsufficient phenotypes in neuronal subpopulations. These variant-specific findings explain observed clinical heterogeneity and confirm the functional impact of patient-derived alleles (PMID:39879987).
Collectively, robust genetic and experimental evidence supports a Strong association between HECTD1 and neurodevelopmental disorder. Inclusion of HECTD1 in diagnostic gene panels for unexplained neurodevelopmental phenotypes is warranted. Key take-home: heterozygous HECTD1 variants result in a reproducible neurodevelopmental disorder driven by haploinsufficiency and variant-specific effects.
Gene–Disease AssociationStrong14 probands including 10 de novo variants ([PMID:39879987]); significant de novo enrichment in 53,305 trios ([PMID:39879987]); concordant functional data Genetic EvidenceStrong10 de novo and 2 compound heterozygous variants in 14 unrelated cases; replication in an independent cohort ([PMID:39879987]) Functional EvidenceModerateConditional neural‐specific knockout mouse recapitulates human phenotypes; C. elegans assays demonstrate variant‐specific functional effects ([PMID:39879987]) |