We demonstrate that beside degron variants that impair the degradation of the encoded protein [11] and downregulation due to promoter hypermethylation [23, 24], dysregulation of AFF3 through gene duplication, heterozygous and biallelic truncating variants, biallelic missense variants, and compound heterozygous truncating/missense variants are associated with cognitive impairment. Here, AFF3 is linked to Cognitive impairment.