The 22q11DS is associated with a highly variable clinical phenotype with more than 180 described features (Robin and Shprintzen, 2005) (Figure 1.3). The 22q11DS phenotype
Figure 1.2: Schematic illustration of the 3Mb 22q11.2 region including the low copy repeats present in this region. Main types of deletions and genes associated are indicated.
encompasses clinical features ranging from somatic, cognitive to psychiatric manifestations that we will describe in the following sections.
1.2.1 Somatic manifestations
The 22q11DS is associated with various somatic disorders mainly, immunodeficiency (in 75%), cardiac anomalies (in 75%) and palatal abnormalities (in 50%) (See for a review McDonald-McGinn et al., 2015).
Cardiovascular abnormalities are generally visible in the prenatal or neonatal period and are the first signs leading to diagnosis. They also represent the main cause of mortality in children with 22q11DS (87%). Main abnormalities include: tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B and ventricular septal defect.
Immunodeficienciesare induced by thymic hypoplasia and impaired T cell production, both leading to various chronic infections.
Palatal abnormalitiesmainly include cleft palate. In most cases submucous cleft palate and bifid uvula are observed, while overt cleft palate are scarcely reported (Bassett et al., 2011). Palatal abnormalities lead to velopharyngeal dysfunction, abnormal nasal resonance
or articulation errors.
Others somatic manifestations include endocrine anomalies (hypocalcemia in 50-65%), gastrointestinal abnormalities (30%) and many others such as facial malformations or growth retardation.
Figure 1.3: Organs and systems affected in individuals with 22q11DS (from NcDonald-McGinn et al., 2015).
1.2.2 Cognitive manifestations
A wide range of cognitive impairments is observed in the 22q11DS population. Cognitive deficits in children with 22q11DS represent a main concern of parents in view of their impact on educational and vocational trajectories. Global intellectual functioning has been largely studied in the context of the syndrome. Whereas the level of intellectual functioning appears to follow a normal distribution, there is an approximately 30-point shift to the left in indi-viduals with 22q11DS compared to the general population. Patients with 22q11DS hence have a mean full scale IQ around 70-75, with an intellectual level ranging from borderline (55%, ¿70) to mild intellectual disability (45%, IQ 55-70). A discrepancy between verbal abilities (VIQ) and perceptual reasoning abilities is found during early childhood whereas this divergence seems less evident with age, due to a decline in the verbal domain. Recently, a multisite study from the International Consortium on Brain and Behavior in 22q11.2 Dele-tion Syndrome (IBBC), showed a decline in IQ over time, particularly in the verbal domain.
A steeper decline for patients with 22q11DS diagnosed with a psychotic disorder was found, suggesting that IQ decline - and VIQ decline in particular - is predictive of psychosis in this syndrome. Beyond a global decrease of intellectual efficiency, specific deficits in some cognitive domains are also observed in 22q11DS individuals. For instance, visuospatial diffi-culties are also commonly found in 22q11DS. Previous studies showed impaired visuospatial perception and memory in patients with 22q11DS (Azuma et al., 2009; Bearden et al., 2001;
Bostelmann et al., 2016; Henry et al., 2002; Simon et al., 2005, 2008; Wong et al., 2014), which seems related to alterations in frontal and parietal regions (Azuma et al., 2009; Si-mon et al., 2008). Another domain of relative weakness in the 22q11DS profile is executive function. Executive functions are higher order skills including: initiation, inhibition, set shifting, working memory, planning used for the execution and regulation of cognitive and behavioral actions (Gioia et al., 2010). To date, impairment in cognitive flexibility and working memory have been described in patients with 22q11DS (Azuma et al., 2009), while more controversial findings for inhibition have been reported (McCabe et al., 2014; Shapiro et al., 2013). Furthermore, a longitudinal study from our group highlighted that working memory and verbal fluency do not gradually increase with age in patients with 22q11DS compared to what is observed in healthy controls (Maeder et al., 2016). Social cognitive deficits represent an additional feature of the 22q11DS cognitive profile (for a review, seee Norkett et al., 2017). Social cognition encompasses the various processes that underlie social interaction. In patients with 22q11DS, a clear impairment in emotion processing and high order theory of mind (TOM) has been reported. Indeed, several studies have demonstrated difficulties of face recognition and emotion identification in patients with 22q11DS. These deficits seem related to atypical face processing, characterized by shorter scanpath lengths, fewer fixations and less time spent on relevant facial features (eyes, nose, mouth) that has been well established in the 22q11DS (Campbell et al., 2010; Franchini et al., 2016; McCabe et al., 2011; Zaharia et al., 2018). A few studies have also reported difficulties of TOM com-petences in patients with 22q11DS (Badoud et al., 2017; Campbell et al., 2015; Ho et al., 2012; Jalbrzikowski et al., 2012, 2014). In schizophrenia, social cognition processes have been
hypothesized as putative contributors in the expression of negative symptoms (Kirkpatrick et al., 2006). The role of social cognition processes in negative symptoms emergence thus progressively became a focus of interest in the field of psychosis. For this reason, a part of this project will focus on social cognition, a summary of the socio-cognitive deficits observed in schizophrenia and the 22q11DS and their link with negative symptoms will therefore be presented in details in the chapter 3 section 2.2.
1.2.3 Psychiatric manifestations
The psychiatric phenotype of 22q11DS has been extensively described in the literature.
From a general point of view, a higher rate of psychiatric disorders in patients with 22q11DS compared to the general population has been consistently reported. Recently, a large study conducted in collaboration with the IBBC, which included 1400 participants allowed to char-acterize the prevalence of major psychiatric diagnoses over time in 22q11DS (Schneider et al., 2014a). By investigating trajectories of major psychiatric disorders across four time points, the authors found that attention deficit hyperactivity disorder (ADHD) was the most com-mon diagnosis in children with 22q11DS (37%). Anxiety and mood disorders were present at all ages. While anxiety disorders were more frequent in children and adolescents, major de-pressive disorders and schizophrenia spectrum disorders were more prevalent in adults with 22q11DS.
Schizophrenia spectrum disorders and psychotic symptoms
Schizophrenia spectrum disorders appear highly prevalent in patients with 22q11DS af-fecting approximately 10% of adolescents and 40% of individuals over 25 years of age (Schnei-der et al., 2014a) (Figure 1.4). Literature demonstrated that patients with 22q11DS have a 30-fold increased risk to develop schizophrenia compared to the general population (Gothelf et al., 1999; Green et al., 2009; Murphy et al., 1999; Schneider et al., 2014a). Additionally, psychotic disorders such as schizoaffective disorder, schizophreniform disorder, delusional disorder, brief psychotic disorder have also been reported in patients with 22q11DS but are less common (Schneider et al., 2014a). Others studies demonstrated that many patients with 22q11DS do not fill the criteria for a schizophrenia spectrum disorders but still present high rates of attenuated psychotic symptoms (Baker and Skuse, 2005; Debban´e et al., 2006;
Schneider et al., 2014a). Moreover, psychotic symptoms in 22q11DS appear similar to other types of schizophrenias (McDonald-McGinn et al., 2015). Indeed, as in schizophrenia, pa-tients with 22q11DS present distinct positive and negative symptoms, which will be described in more details in the next chapter. While positive symptoms are experienced by 23% to 45% of adolescents (Schneider et al., 2012; Stoddard et al., 2010), negative symptoms appear more predominant as present in approximately 60 to 80% of adolescents and young adults with 22q11DS (Schneider et al., 2012; Stoddard et al., 2010).
Figure 1.4: Prevalence of schizophrenia spectrum disorders over age in individuals with 22q11DS (from Schneider et al., 2014)
The 22q11DS as a model of schizophrenia
In light of the high prevalence of schizophrenia spectrum disorders reported in patients with 22q11DS, the syndrome is considered as a valuable model of schizophrenia. Indeed, studies indicate that the risk for schizophrenia in patients with 22q11DS is about 20 to 25 times higher than in the general population (See for a review Bassett et al., 2000). In addition, one study found that the prevalence of 22q11DS among schizophrenia patients is about 0.5% to 1.2% (See for an overview Hoogendoorn et al., 2008) , which is much higher than the prevalence estimated in the general population. Furthermore, there are neurode-velopmental and genetic evidences supporting the 22q11DS as a model of schizophrenia. On one hand, neurodevelopmental studies demonstrated common features between patients with 22q11DS and those with schizophrenia including developmental delays, speech difficulties, coordination deficits, blunted affect and social withdrawal (See for a review Bassett et al., 2000). Similar brain anomalies are also reported in both disorders such as ventricular en-largement, decreased brain volume (Amelsvoort et al., 2004), midline defects (Chow et al., 1999) and white matter alterations (Amelsvoort et al., 2004; Chow et al., 1999). In addi-tion, the pathogenesis of the two disorders seems to involve the same mechanism, namely abnormal neuronal migration (Bassett and Chow, 2008). On another hand, genetic studies
found that both schizophrenia and 22q11DS results from de novo mutations (Dallapiccola et al., 1996). Moreover, several genes located with the 22q11.2 locus have been related to risk of schizophrenia (Karayiorgou and Gogos, 2004). All these findings have led to the proposal that 22q11DS is a genetic model of neurodevelopmental mechanisms involved in the pathogenesis of schizophrenia.