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  3. HECTD1
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Intellectual disability syndromic and non-syndromic

Gene: HECTD1

Green List (high evidence)
HECTD1 (HECT domain E3 ubiquitin protein ligase 1)
EnsemblGeneIds (GRCh38): ENSG00000092148
EnsemblGeneIds (GRCh37): ENSG00000092148
HECTD1 is in 3 panels

1 review

Chirag Patel (Genetic Health Queensland)

Green List (high evidence)

14 unrelated individuals (identified through GeneMatcher) with 15 variants of uncertain significance (VUS) in HECTD1 (10 missense, 3 frameshift, 1 nonsense, and 1 splicing variant). Of the 15 different variants in HECTD1, 10 occurred de novo, 3 had unknown inheritance, and 2 were compound heterozygous. All variants were absent in gnomAD, and HECTD1 is highly intolerant to loss-of-function variation (loss-of-function-intolerant score of 1). Clinical presentation was variable developmental delay, intellectual disability, autism spectrum disorder, ADHD, and epilepsy.

The one individual with compound heterozygous variants had growth impairment along with NDD. The variants were inherited from apparently healthy parents, suggesting that genetic or environmental modifiers may be required to develop the phenotype.

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.

HECT-domain-containing protein 1 (HECTD1) mediates developmental pathways, including cell signalling, gene expression, and embryogenesis. 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 2 missense variants and 1 nonsense variant in C. elegans revealed dominant effects, including either change-of-function or loss-of-function/haploinsufficient mechanisms.
Sources: Literature
Created: 5 Feb 2025, 11:01 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neurodevelopmental disorder MONDO:0700092

Publications

Created: 5 Feb 2025, 11:01 p.m.

Panel version: 1.59

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Neurodevelopmental disorder MONDO:0700092
Clinvar variants
Variants in HECTD1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

7 Feb 2025, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: hectd1 has been classified as Green List (High Evidence).

5 Feb 2025, Gel status: 3

Entity classified by Genomics England curator

Chirag Patel (Genetic Health Queensland)

Gene: hectd1 has been classified as Green List (High Evidence).

5 Feb 2025, Gel status: 3

Entity classified by Genomics England curator

Chirag Patel (Genetic Health Queensland)

Gene: hectd1 has been classified as Green List (High Evidence).

5 Feb 2025, Gel status: 3

Entity classified by Genomics England curator

Chirag Patel (Genetic Health Queensland)

Gene: hectd1 has been classified as Green List (High Evidence).

5 Feb 2025, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Chirag Patel (Genetic Health Queensland)

gene: HECTD1 was added gene: HECTD1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature Mode of inheritance for gene: HECTD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HECTD1 were set to PMID: 39879987 Phenotypes for gene: HECTD1 were set to Neurodevelopmental disorder MONDO:0700092 Review for gene: HECTD1 was set to GREEN