This study aimed to characterize the relationship between insistence on sameness (IS), executive functioning (EF) and anxiety among individuals with "PTEN" mutations and individuals with macrocephalic ASD. The sample included 38 individuals with "PTEN" mutation and ASD diagnosis ("PTEN"-ASD; M[subscript age] = 8.93 years, SD[subscript age] = 4.75), 23 with "PTEN" mutation without ASD ("PTEN"-no ASD; M[subscript age] = 8.94 years; SD[subscript age] = 4.85) and 25 with ASD and macrocephaly but with no "PTEN" mutation (Macro-ASD; M[subscript age] = 11.99 years; SD[subscript age] = 5.15). The final model accounted for 45.7% of variance in IS, with Set-Shifting EF subdomain as a unique independent predictor (t = 4.12, p < 0.001). This investigation provides the first preliminary evidence for the EF-anxiety-IS interrelationship in individuals with "PTEN" mutations and with macrocephalic ASD. [This article was written on behalf of the Developmental Synaptopathies Consortium.]