HECW2

Inheritance Pattern: AD

Disease ID:MONDO:0014995

Submitter: Illumina

The HECW2 gene is located on chromosome 2 at 2q32.3 and encodes HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2, a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. E3 ligases function in the control of ubiquitin-mediated protein degradation. HECW2 also plays a role in the function of neural crest cells by regulating glial cell line-derived neurotrophic factor (GDNF)/Ret signaling. HECW2 was first reported in relation to an autosomal dominant neurodevelopmental disorder in 2016 (27334371: Halvardson et al. 2016). Evidence supporting this gene-disease relationship includes case-level data and limited experimental data. Variants in this gene have been reported in at least eight individuals in three publications (27389779: Berko et al. 2017; 29807643: Ullman et al. 2018; 27334371: Halvardson et al. 2016). At least four unique missense variants have been identified, with at least two recurrent variants noted: p.Arg1191Gln and p.Arg1330Trp. All variants occurred de novo. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by limited experimental evidence. Expression is ubiquitous but high in brain (25613900: Uhlén et al. 2015); at least two other HECT domain E3 ubiquitin ligases have also been associated with disease in humans; HECW2 interacts with other protein products associated with related clinical phenotypes (24163370: Lu et al. 2013). In summary, there is strong evidence to support the relationship between HECW2 and an autosomal dominant HECW2-related neurodevelopmental disorder. Additional experimental evidence is needed to reach a definitive classification.

Inheritance Pattern: AR

Disease ID:MONDO:0014995

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0014995

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

The *HECW2* gene encodes an E3 ubiquitin ligase involved in the control of ubiquitin-mediated protein degradation. Heterozygous missense variants in *HECW2* cause autosomal dominant complex neurodevelopmental disorder. In addition, there have been three reports of biallelic truncating variants in *HECW2* in individuals with neurodevelopmental disorders. This curation concerns the relationship between *HECW2* and autosomal recessive complex neurodevelopmental disorder. *HECW2* was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2022 (Krami et al., PMID: 35487419). Three homozygous variants (nonsense, splice and frameshift) that have been reported in three probands in three publications (PMIDs: 35487419, 35753050, 40812465) are included in this curation. The clinical features of the three affected girls are highly conserved and include profound developmental delay, intellectual disability, severe hypotonia, early-onset seizures, and failure to thrive. At the time of the report, at ages 4-6 years, they had not achieved head control, were unable to sit, walk, or speak, and had no visual tracking. MRI showed variable levels of brain atrophy. One girl died suddenly at age 4 years. The mechanism of pathogenicity is reported to be loss of function. A splice variant that led to exon skipping and in‐frame deletion exhibited a two-fold increase in RNA expression, while the protein expression level was reduced by 60%, suggesting a partial loss‐of‐function mechanism (PMID: 35753050). This gene-disease relationship is further supported by experimental evidence, including biochemical function, protein interaction and an animal model. Transcriptional knockdown of zebrafish *hecw2a* led to early brain development abnormalities (PMID: 33205896). Numerous genes encoding E3 ubiquitin protein ligases have been involved in neurodevelopmental disorders (e.g., *HUWE1*, *UBE3A*, *UBE3B*, *UBE3C*, *TRIP12*, *TRIM8*, *HECTD1*, *HECTD4*). HECW2 binds to TP73 and enhances its transcriptional activity by increasing its stability (PMID: 12890487); null variants in *TP73* are associated with autosomal recessive primary ciliary dyskinesia-47 and lissencephaly. In summary, there is moderate evidence to support the relationship between *HECW2* and autosomal recessive complex neurodevelopmental disorder. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 18, 2023. It was re-evaluated on April 22, 2026 (SOP Version 12). As a result of this reevaluation, the classification increased from Limited to Moderate with the addition of an affected individual (PMID: 40812465).

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

The *HECW2* gene encodes an E3 ubiquitin ligase involved in the control of ubiquitin-mediated protein degradation. *HECW2* was first reported in relation to complex neurodevelopmental disorder in 2017 (Berko et al., PMID: 27389779). To date, at least 20 missense variants in *HECW2*, including 4 recurrent variants, have been reported in individuals with developmental delay/intellectual disability (100%), developmental language disorder (100%) and hypotonia (100%). Other common features are behavioral problems (89%) including autism spectrum disorder or autistic features, vision problems (84%), motor coordination/movement abnormalities (75%), gastrointestinal issues (70%), and seizures (61%). All reported variants with known inheritance are *de novo* missense variants; the majority are located in the C-terminal area of the protein, and particularly in the C-terminal HECT domain of HECW2. The disease mechanism of HECW2-related autosomal dominant complex neurodevelopmental disorder is still unclear. Of note, homozygous *HECW2* loss-of-function variants have been reported in two unrelated individuals with a severe neurodevelopmental phenotype (PMIDs: 35487419, 35753050); the disease relationship in these cases will be curated separately. This gene-disease relationship is further supported by experimental evidence. Transcriptional knockdown of zebrafish hecw2a led to early brain development abnormalities (PMID: 33205896). Co-immunoprecipitation experiments and *in vitro* pull-down assays revealed that HECW2 bound to TP73 and activated its function by increasing its stability (PMID: 12890487). Null variants of *TP73* are associated with autosomal recessive primary ciliary dyskinesia-47 and lissencephaly. In summary, there is definitive evidence supporting the relationship between *HECW2* and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 18, 2023 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0014995

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014995

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014995

Submitter: G2P