Investigating the role of a novel hemizygous FAAH2 variant in neurological and metabolic disorders

Fatty acid amide hydrolase 2 (FAAH2) is an enzyme involved in the degradation of endocannabinoids in humans. Altered FAAH2 activity has been implicated in various neurological and psychiatric conditions. We describe a male patient presenting with anxiety disorder, autistic-like traits, and borderline intellectual functioning (BIF), as well as metabolic disturbances including obesity and hepatic steatosis. Trio-based whole-exome sequencing (WES) identified the novel hemizygous c.988C > A (p.Gln330Lys) variant in the X-linked FAAH2 gene, which currently lacks an associated MIM phenotype. Structural modelling suggested that the variant induces multiple alterations in the amidase signature (AS), a key functional domain of the enzyme. These findings contribute to the emerging evidence supporting FAAH2 as a candidate gene for a neurodevelopmental phenotype with metabolic involvement, consistent with an X-linked inheritance pattern.