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 two 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. In 2022, Krami et al. reported a homozygous nonsense HECW2 variant in a 5 year old proband from a Moroccan consanguineous family with severe developmental delay, intellectual disability, absent speech, hypotonia, inability to sit or walk, and generalized tonic-clonic seizures starting at 1 month of age (PMID: 35487419). In addition, Rodriguez-Garcia et al. reported a homozygous intronic HECW2 variant in a girl with severe developmental delay, early-onset drug‐resistant epilepsy and hypotonia; she never achieved any neurodevelopmental milestones and died suddenly at age 4 years (PMID: 35753050). This variant disrupted the splice donor site of intron 22 and caused the elimination of exon 22, leading to an in‐frame deletion of 51 amino acids in the HECW2 protein. Functional studies showed a twofold increase in RNA expression, while the protein expression level was reduced by 60%, suggesting a partial loss‐of‐function mechanism of pathogenesis (PMID: 35753050).
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 limited evidence at this time to support the relationship between HECW2 and autosomal recessive complex neurodevelopmental disorder. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 18, 2023 (SOP Version 9).
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