title: The role of COMT and plasma proline in the variable penetrance of autistic spectrum symptoms in 22q11.2 deletion syndrome.
abstract: This paper examines how COMT158genotypes and plasma proline levels are associated with variable penetrance of social behavioural and social cognitive problems in 22q11.2 deletion syndrome (22q11DS). Severity of autistic spectrum symptoms of 45 participants with 22q11DS was assessed using the Autism Diagnostic Interview Revised. Face and facial emotion recognition was evaluated using standardized computer-based test-paradigms. Associations with COMT158genotypes and proline levels were examined. High proline levels and poor face recognition in individuals with the COMTMETallele, and poor facial emotion recognition, explained almost 50% of the variance in severity of autism symptomatology in individuals with 22q11DS. High proline levels and a decreased capacity to break down dopamine as a result of the COMTMETvariant are both relevant in the expression of the social phenotype in patients. This epistatic interaction effect between the COMT158genotype and proline on the expression of social deficits in 22q11DS shows how factors other than the direct effects of the deletion itself can modulate the penetrance of associated cognitive and behavioural outcomes. These findings are not only relevant to our insight into 22q11DS, but also provide a model to better understand the phenomenon of variable penetrance in other pathogenic genetic variants.
authors.affiliation: Department of Clinical Child and Adolescent Studies, Faculty of Social and Behavioural Sciences, Leiden University, Leiden, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Hidding
authors.affiliation: Department of Clinical Child and Adolescent Studies, Faculty of Social and Behavioural Sciences, Leiden University, Leiden, The Netherlands.|Leiden Institute of Brain and Cognition, Leiden, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Swaab
authors.affiliation: Department of Clinical Child and Adolescent Studies, Faculty of Social and Behavioural Sciences, Leiden University, Leiden, The Netherlands. LSonneville@fsw.leidenuniv.nl.|Leiden Institute of Brain and Cognition, Leiden, The Netherlands . LSonneville@fsw.leidenuniv.nl.
authors.forename: L M J
authors.initials: LM
authors.lastname: de Sonneville
authors.affiliation: Department of Psychiatry, Brain Center Rudolph Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: van Engeland
authors.affiliation: Department of Psychiatry, Brain Center Rudolph Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: J A S
authors.initials: JA
authors.lastname: Vorstman
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D002648:Child; D004062:DiGeorge Syndrome / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D004298:Dopamine; D004843:Epistasis, Genetic; D005145:Face; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D019683:Penetrance; D011392:Proline / Q000097:blood; D017384:Sequence Deletion; D012919:Social Behavior
chemical_list: D011392:Proline; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; D004298:Dopamine
keywords: 22q11.2 deletion; autism symptomatology; catechol-O-methyltransferase; plasma proline; social cognition