- Top of page
- MATERIALS AND METHODS
- Supporting Information
Initially described as a syndrome by DiGeorge  and determined to be the result of the 22q11.2 microdeletion [Driscoll et al., 1992], 22q11DS is estimated to occur in 1/4,000 live births [Devriendt et al., 1998; Botto et al., 2003]. It is characterized by a host of congenital abnormalities including congenital heart disease (CHD), palatal defects, immune deficiencies and thymic hypoplasia [Ryan et al., 1997; Botto et al., 2003; McDonald-McGinn and Sullivan, 2011]. Most affected individuals have deficits in language, motor, visual-spatial processing, executive function, memory, and social cognition [Golding-Kushner et al., 1984; Gerdes et al., 1999; Bearden et al., 2001; Kiley-Brabeck and Sobin, 2006; De Smedt et al., 2007; Ousley et al., 2007; Van Aken et al., 2007; Goldenberg et al., 2012; Howley et al., 2012]. High prevalence of psychiatric disorders has been associated with the syndrome. Anxiety disorder, major depressive disorder, attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder may emerge in childhood [Swillen et al., 1999; Gothelf et al., 2004; Niklasson et al., 2005; Antshel et al., 2006; Green et al., 2009; Jolin et al., 2009, 2012; Fabbro et al., 2012; Tang et al., 2013] and schizophrenia spectrum features may emerge in adolescence and early adulthood [Murphy et al., 1999; Bassett et al., 2003; Gothelf et al., 2007; Vorstman et al., 2006; Green et al., 2009; Stoddard et al., 2010; Hooper et al., 2013; Tang et al., 2013].
Multiple congenital, psychiatric and neurocognitive phenotypes observed in 22q11DS enable investigation of interactions among genetic vulnerability and congenital anomalies that may impact intrauterine brain development and be associated with psychiatric disorders. CHD is one of the most common defects in 22q11DS and is reported in approximately 60–75% of cases [Marino et al., 1999, 2012], compared to about 6/1,000 live births in the US general population [Hoffman and Kaplan, 2002; Hoffman et al., 2004]. The 22q11.2 deletion is found in increased frequencies in those born with various CHDs such as interrupted aortic arch, truncus arteriosus, conoventricular septal defects and tetralogy of Fallot (TOF) [Agergaard et al., 2012]. With advances in corrective and palliative surgical techniques, the survival rates of infants born with CHDs have dramatically improved [Gilboa et al., 2010; Marino et al., 2012].
Non-deleted individuals with CHDs who survive to infancy or toddler years often have neurodevelopmental delays, while those who survive to pre-school or school age have higher rates of learning difficulties, ADHD, anxiety disorder, and behavioral problems [Rogers et al., 1995; Forbess et al., 2002; Wernovsky et al., 2005; Karsdorp et al., 2007; Shillingford et al., 2008; Kovacs et al., 2009]. A growing literature suggests that severity of CHDs as well as pre- and peri-operative factors are implicated in early brain development and may confer neuropsychiatric vulnerability [Glauser et al., 1990; Fallon et al., 1995; Miller et al., 1995; Bellinger et al., 1999; Marino et al., 2012]. Presently, studies focus primarily on early neurodevelopmental outcomes during infancy or pre-school age. There is a lack of research examining psychiatric disorders in school-aged children or adolescents. Similarly, studies in 22q11DS have been limited to early neurodevelopmental outcomes and have not consistently found a correlation between the CHD status and neurodevelopmental measures [Maharasingam et al., 2003; Gothelf et al., 2004; Swillen et al., 2005; Atallah et al., 2007; Carotti et al., 2008; Cheung et al., 2013]. These studies suggest that 22q11.2 deletion alone may substantially contribute to neurodevelopmental delays and perhaps to neuropsychiatric vulnerability. Neuroimaging studies report that CHDs in 22q11DS correlate with reduction of total cerebral volume and certain cortical regions, and abnormal gyrification, implicating a role for CHDs in neurodevelopment in 22q11DS [Schaer et al., 2009, 2010].
We examined whether the high prevalence of psychiatric disorders in 22q11DS was partly due to effects of CHD on early neurodevelopment. We compared the prevalence of psychiatric disorders, across three clinical groups: 22q11DS with a CHD, 22q11DS without a CHD, and non-deleted with a CHD. We chose the age range of 8–14 years old as many psychiatric disorders are diagnosed during this period in 22q11DS. We also investigated the effect of CHDs on cognition and applied the Computerized Neurocognitive Battery [Gur et al., 2010, 2012]. CNB assesses five cognitive domains commonly impaired in 22q11DS—executive, memory, language, social, and sensorimotor. We hypothesized that 22q11DS with CHDs group would be associated with a higher prevalence of psychiatric disorders and neurocognitive impairments than 22q11DS without a CHD or non-deleted individuals with CHDs.
- Top of page
- MATERIALS AND METHODS
- Supporting Information
Individuals with 22q11DS have high neuropsychiatric and medical burdens. CHD is one of the most common medical conditions in 22q11DS and has been independently implicated in early neurodevelopmental delays in non-deleted populations. We hypothesized that in 22q11DS, CHDs may potentiate the neuropsychiatric burden manifested later in development. We therefore examined the association between CHDs and neuropsychiatric outcomes in school-age children with 22q11DS. We included a 22q-noCHD comparison group to control for the 22q11.2 deletion background and examine the effect of CHD alone.
We found that individuals with 22q11DS are at increased risk for psychiatric disorders and neurocognitive deficits regardless of CHD status. The majority of participants with 22q11DS had at least one psychiatric diagnosis. In agreement with other studies [Gothelf et al., 2004, 2007; Green et al., 2009; Niklasson et al., 2009; Jolin et al., 2012; Tang et al., 2013], they had high prevalence of ADHD, anxiety disorders and psychosis spectrum, which was most common. The majority of psychosis spectrum individuals exhibited subthreshold symptoms rather than threshold psychotic disorders. Our rate of subthreshold psychosis was higher than previously reported and this may reflect ascertainment bias, variability in assessment methods and the instability of psychosis phenomenon in developing children. SIPS ratings have not been validated in developmentally delayed children. Although it is likely sensitive in detecting subthreshold symptoms in children, the SIPS ratings may not be specific enough and a portion of subthreshold symptoms observed is likely better accounted for by developmental challenges and high level of anxiety in 22q11DS population. We plan to address this issue with a larger sample of 22q11DS in the future.
Notably, the prevalence rates of all psychiatric disorders evaluated were comparable between the two 22q11DS groups. ADHD and psychosis spectrum were significantly higher in the 22q11DS groups than in the non-syndromic CHD-only group, but there was no such contrast for anxiety disorders or major depressive disorder. This lack of a CHD effect on psychopathology in 22q11DS could be due to several possibilities. The neurodevelopmental vulnerability conferred by 22q11.2 deletion may dominate and obscure the effect of CHD. These attenuated effects of CHD are detectable by neuroimaging studies [Schaer et al., 2009, 2010]. However, while these studies demonstrate effect of CHD on brain morphology, it is unclear how they correlate with neuropsychiatric outcomes. CHD is one of many modifying factors involved in the development of psychiatric disorders in 22q11DS. Sample size and time limitations currently preclude investigation of other potential risk factors such as additional co-occurring medical conditions, family history of mental illness and psychosocial stressors. We are likewise unable to account for potential protective factors, such as early mental health utilization, consistent medical care and supportive family environment. The effects of CHD observed in early neurodevelopment may be compensated later in development. Previous studies examining non-deleted school-age children with CHD showed higher rates of learning difficulties, ADHD, anxiety, and behavioral issues and suggest that the CHD effect may persist into later in development [Karsdorp et al., 2007; Shillingford et al., 2008; Marino et al., 2012]. However, it is difficult to draw a conclusion due to the cross-sectional nature and variability of assessment tools used in these studies.
We observed no difference in the rates of anxiety disorder and major depressive disorder among the CHD-only and 22q11DS groups. The prevalence of major depressive disorder was relatively low in our 22q11DS sample compared to other studies [Fabbro et al., 2012; Jolin et al., 2012] and may reflect ascertainment and assessment bias. In agreement with other studies [Karsdorp et al., 2007; Spijkerboer et al., 2008; Marino et al., 2012], anxiety disorders were elevated in the CHD-only group relative to the expected rate in the general population; thus, the prevalence of anxiety disorders is comparable to the levels observed in the 22q11DS groups.
Similar to the findings in psychopathology, we did not observe significant differences in neurocognitive profiles between the 22q11DS groups. Moreover, 22q11DS groups showed a robust reduction in accuracy compared to both CHD-only and TD individuals, suggesting that the observed neurocognitive impairments in 22q11DS are not attributable to cardiac anomalies and their sequelae. 22q11DS groups were particularly impaired in social cognition domain, performing poorly in both accuracy and speed. CHD-only group also performed poorly in social cognition but only in speed. This difference in the type of impairment suggests that different brain regions could be affected in these groups. Notably, our neurocognitive data showed no clear deficit in the CHD-only group compared to the TD group, suggesting that the effect of CHD or heart surgery status may not persist into school-age. However, the type of CHD and severity of complications related to surgery may affect the cognitive outcomes. Due to a relatively small sample size, we could not match the study groups to specific CHD.
Previous studies have suggested that the complexity of CHD and extent of hemodynamic compromise measured by perinatal and perioperative hypoxia in non-syndromic population is correlated with worsening developmental delays and functional outcomes [Karsdorp et al., 2007; Marino et al., 2012]. In the current study, we did not measure these aspects of CHD and therefore could not investigate their relationship to neuropsychiatric outcome. It will be important to consider such measures in future studies.
Because the study focused on brain-behavior measures, we included individuals without significant intellectual disabilities and the results may not be generalized to patients with more marked impairment. Similarly, the age range of 8–14 precludes generalization to individuals with the deletion younger or older than the selected range. Notably, the pattern of neurocognitive deficits observed in this sample is similar to that reported in younger children and in older adolescents and young adults.