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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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