Genetic subtyping and its implications for clinical management: The case of 22q11.2 syndrome

Objectives: The 22q11.2 deletion syndrome (22qDS), mostly caused by the common deletion (LCR-A-D) including TBX and COMT genes, is highly associated with congenital anomalies and endocrine dysfunctions accompanied by schizophrenia-like psychoses and autism spectrum disorders. The distal deletion (LCR-D-H) comprises the MAPK1 gene and is associated with specific heart defects and the presence of anxiety disorders. The relatively rare central deletion (LCR-B-D) encompasses the CRKL gene and predominantly shows renal/urogenital anomalies in combination with autistic-like behaviours. Participants and Methods: Thirty patients with genetically proven and subtyped 22q11DS were referred to the Dutch national outpatient facility specialized in psychopathology and genetics for detailed cognitive neuropsychiatric assessment in order to ascertain the most appropriate neuropsychological and psychopharmacological strategy. Results: Apart from one distal and one central deletion, common deletion was found in 28 patients. They presented with a variable level of intellectual disability. Patients with common deletion had a history of relapsing schizophrenia-like psychoses, partial or nonresponsive to conventional antipsychotics, and often accompanied by anxieties and mood instability. The patient with distal deletion displayed anxiety symptoms, whereas in the one with central deletion, autistic-like behaviour was present. Most patients with common deletion could effectively be treated with targeted contextual measures and clozapine or quetiapine, often combined with valproic acid. The patient with distal deletion showed full remission upon treatment with citalopram whereas in the patient with central deletion, behaviour strongly improved upon contextual-neuropsychological and behavioural measures only. Discussion: Clinical management of patients with 22q11DS should be guided primarily by its genetic subtype