Submission Details

APC2 was first reported in relation to autosomal recessive lissencephaly spectrum disorders by Lee et al. in 2019 (PMID 31585108). Individuals with lissencephaly spectrum disorders related to APC2 pathogenic variants present with posterior predominant lissencephaly +/- corpus callosum dysgenesis, hypoplasia of the cerebellum, severe developmental delay , epilepsy with myoclonic or generalized tonic-clonic seizures. At least 9 unique variants predicted to cause loss of function have been reported in humans in association with autosomal recessive lissencephaly spectrum disorders . Evidence supporting this gene-disease relationship includes experimental data implicating APC2 plays a role in microtubule function at the axonal growth cone and Apc2 -/- mouse models demonstrating defects in the cortical lamina, as well as the cerebellum. Of note, this gene has also been implicated in Sotos Syndrome Type 3 which features intellectual disability and characteristic facial features. This association will be assessed separately in the future. Three years have elapsed since the first association between APC2 and lissencephaly spectrum disorders, so a definitive classification is warranted. This classification was approved by the ClinGen Brain Malformations gene curation expert panel on October 11, 2022 (SOP Version 9).