Submission Details

EXOC2 was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2020 (Van Bergen et al., PMID:32639540). Phenotypic features reported in affected individuals include developmental delay, dysmorphisms, intellectual disability, brain abnormalities, and poor motor skills. Three variants (1 nonsense and 2 missense) have been reported in the literature. One variant in EXOC2, reported in 2 homozygous individuals in one consanguineous family is included in this curation (PMID:32639540).

This gene-disease relationship is also supported by rescue in patient cells and model organism experiments. Defects in protein expression, global vesicle fusion rates, and cargo delivery were restored to wild-type levels upon transduction of wild-type EXOC2 lentiviral particles. Additionally, knockout of EXOC2 expression in Drosophila melanogaster demonstrated impairment of neuromuscular junction growth, neurite outgrowth, and vesicle trafficking to the plasma membrane (PMIDs: 32639540, 12575951).

Of note, an additional proband with compound heterozygous missense variants has been reported (PMID: 32639540). However, there is conflicting experimental functional evidence using patient cells. Out of caution, evidence for this proband and the missense variants has not been scored as additional evidence is needed to further demonstrate a relationship between these missense variants and disease.

In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on August 1, 2023 (SOP Version 9).