Human Gene Module / Chromosome 14 / HECTD1

HECTD1HECT domain E3 ubiquitin protein ligase 1

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 7
Rare Variants / Common Variants
32 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
14q12
Associated Disorders
-
Relevance to Autism

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
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HECTD1 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
3 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
4 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Cirnigliaro M et al. (2023) Yes -
7 Primary - Gazelle Zerafati-Jahromi et al. (2025) No ASD, ADHD, ID, epilepsy/seizures
Rare Variants   (32)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2443A>G p.Thr815Ala missense_variant De novo - - 28714951 Lim ET , et al. (2017)
c.227G>A p.Arg76His missense_variant Familial Maternal - 30564305 Guo H , et al. (2018)
c.2919A>G p.Glu973= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.459C>T p.Asp153= synonymous_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.631G>A p.Ala211Thr missense_variant Familial Maternal - 30564305 Guo H , et al. (2018)
c.5227A>G p.Ile1743Val missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2936C>T p.Pro979Leu missense_variant Familial Maternal - 30564305 Guo H , et al. (2018)
c.3529T>C p.Trp1177Arg missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.3250G>A p.Ala1084Thr missense_variant Familial Paternal - 30564305 Guo H , et al. (2018)
c.3359G>A p.Arg1120His missense_variant Familial Paternal - 30564305 Guo H , et al. (2018)
c.4552G>T p.Val1518Leu missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1289_1291del p.Ser430del inframe_deletion De novo - Simplex 35982159 Zhou X et al. (2022)
c.5270G>T p.Arg1757Leu missense_variant Unknown Not maternal - 30564305 Guo H , et al. (2018)
c.5467G>A p.Val1823Ile missense_variant Unknown Not maternal - 30564305 Guo H , et al. (2018)
c.3670G>T p.Gly1224Ter stop_gained De novo - - 39879987 Gazelle Zerafati-Jahromi et al. (2025)
c.1289_1291del p.Ser430del inframe_deletion De novo - Simplex 25363768 Iossifov I et al. (2014)
c.140C>T p.Thr47Ile missense_variant Unknown - - 39879987 Gazelle Zerafati-Jahromi et al. (2025)
c.476A>G p.His159Arg missense_variant Familial - - 39879987 Gazelle Zerafati-Jahromi et al. (2025)
c.2764dup p.Thr922AsnfsTer6 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.710T>C p.Leu237Ser missense_variant De novo - Simplex 39879987 Gazelle Zerafati-Jahromi et al. (2025)
c.1111C>G p.Arg371Gly missense_variant De novo - Simplex 39879987 Gazelle Zerafati-Jahromi et al. (2025)
c.2082C>G p.Phe694Leu missense_variant De novo - Simplex 39879987 Gazelle Zerafati-Jahromi et al. (2025)
c.2349dup p.Asp784ArgfsTer8 frameshift_variant Unknown - - 39879987 Gazelle Zerafati-Jahromi et al. (2025)
c.3346G>A p.Asp1116Asn missense_variant De novo - Simplex 39879987 Gazelle Zerafati-Jahromi et al. (2025)
c.3350T>C p.Ile1117Thr missense_variant De novo - Simplex 39879987 Gazelle Zerafati-Jahromi et al. (2025)
c.3709T>A p.Tyr1237Asn missense_variant De novo - Simplex 39879987 Gazelle Zerafati-Jahromi et al. (2025)
c.3994C>T p.Leu1332Phe missense_variant De novo - Simplex 39879987 Gazelle Zerafati-Jahromi et al. (2025)
c.7135C>T p.Leu2379Phe missense_variant De novo - Simplex 39879987 Gazelle Zerafati-Jahromi et al. (2025)
c.2485dupA p.Thr829fs frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.7433dup p.Leu2478PhefsTer7 frameshift_variant Unknown - - 39879987 Gazelle Zerafati-Jahromi et al. (2025)
c.6536delC p.Ala2179ValfsTer35 frameshift_variant Familial - - 39879987 Gazelle Zerafati-Jahromi et al. (2025)
c.1333-6_1333-4del p.? splice_region_variant De novo - Simplex 39879987 Gazelle Zerafati-Jahromi et al. (2025)
Common Variants  

No common variants reported.

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