The 22q11.2 Deletion Syndrome as a Window into Complex Neuropsychiatric Disorders Over the Lifespan

Abstract

Evidence is rapidly accumulating that rare, recurrent copy number variants (CNVs) represent large effect risk factors for neuropsychiatric disorders. 22q11.2 Deletion Syndrome (22q11DS; Velo-Cardio-Facial Syndrome (VCFS) or DiGeorge Syndrome) is the most common known contiguous gene deletion syndrome, and is associated with diverse neuropsychiatric disorders across the lifespan. One of the most intriguing aspects of the syndrome is the variability in clinical and cognitive presentation: children with 22q11DS have high prevalence of autism spectrum (ASD), attention deficit, and anxiety disorders, as well as psychotic-like features, and up to 30% of adolescents and adults develop schizophrenia-like psychosis. Recently, cases of early-onset Parkinson’s Disease in adults have been reported, collectively suggesting a role for disrupted dopaminergic neurotransmission in the observed neuropsychiatric phenotypes. There is also some evidence that 22q11DS-associated ASD and schizophrenia represent two unrelated phenotypic manifestations, consistent with a neuropsychiatric pleiotropy model. This genetic lesion thus provides a unique model for the discovery of specific genomic risk and (potentially) protective factors for neuropsychiatric disease. Here we provide an overview of neuropsychiatric findings to date, which highlight the value of this syndrome in mapping the developmental trajectory of dimensional phenotypes that traverse multiple diagnostic categories. Potential sources of genetic variability that may contribute to the disorder’s heterogeneous presentation are reviewed. Because of its known genetic etiology, animal models can readily be developed that recapitulate specific aspects of the syndrome. Future research directions involve translational models and potential for drug screenable targets in the context of this human model system.

Diagnose eines 22q11.2-Mikrodeletionssyndroms im Rahmen einer neu aufgetretenen psychotischen Symptomatik

“…Weiters gilt die Mikrodeletion 22q11.2 als der stärkste molekulargenetisch bekannte Risikofaktor für die Entwicklung einer psychotischen Erkrankung [4], wobei in einer rezenten, groß angelegten Untersuchung bei über 40 % der über 25 Jahre alten PatientInnen mit 22q11.2DS eine Schizophrenie-Spektrum-Störung festgestellt werden konnte [4]. Basierend auf diesen Beobachtungen wird das 22q11.2DS als Modellerkrankung für die Pathophysiologie verschiedener neuropsychiatrischer Krankheitsbilder intensiv untersucht [7].…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…Historically, 22q11DS constitutes a major risk factor for a schizophrenia-like condition [138]. Approximately 85% of individuals with 22q11DS have the recurrent 3-Mb deletion, encompassing roughly 60 genes [139]. In the largest study of individuals with 22q11DS, Schneider et al [140] examined the psychiatric profile of 1402 participants (aged 6-68 years) throughout their lifespan.…”

“…COMT may influence cognitive functioning and psychosis [142][143][144]. Epistasis may also occur between COMT and PRODH, and is likely to affect behavior [139]. Heterozygous Tbx1 mice displayed impairments in social interactions, ultrasonic vocalizations, and working memory [145].…”

ISDN2014_0211: An fMRI study of facial emotion processing in children and adolescents with 22q11.2 deletion syndrome

“…While the physical phenotype is variable, commonly reported features include characteristic facial dysmorphology, congenital heart disease, and cleft palate [7,8]. A characteristic behavioural phenotype in 22q11DS has also been described-with high rates of schizophrenia, attention deficit (hyperactivity) disorder (ADD, ADHD) [3,[8][9][10][11][12][13], autistic spectrum disorders, anxiety disorders, and emotional instability [12][13][14][15][16][17]. In addition, children and adults with 22q11DS typically have mild intellectual disabilities and a characteristic cognitive profile-with particular deficits in visual-perceptual function and social and abstract reasoning [3,[17][18][19][20][21][22][23][24][25][26].…”

“…For instance, it has been reported that people with 22q11DS typically show a 'bland affect' with minimal facial expression, in addition to disinhibited and impulsive or serious and shy extremes of behaviour [17,25,30,31]. Furthermore, it has been reported that 20%-50% of children and adolescents in their sample of 22q11DS exhibited some 'autism spectrum problem [13,16,25,[32][33][34][35].' While reported prevalence of autistic spectrum disorder (ASD) among 22q11DS varies widely from study to study, it is nevertheless considerably higher than in the general population which is around 1% to 1.5% [36][37][38][39][40][41][42][43].…”