PTEN and PTEN hamartoma tumor syndrome: As many as 23% of patients with PHTS develop ASD/DD.16 Conversely, 2% to 5% of unselected patients with ASD/DD and as many as 50% of children with ASD and macrocephaly have been found to carry germline PTEN mutations.39 As such, PTEN itself is a syndromic autism gene with well-established roles in nervous system development and neuronal function.40 However, why more than 75% of PTEN mutation carriers do not develop ASD/DD remains a clinical conundrum.