A normative chart for cognitive development in a genetically selected population

Abstract

Certain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cognitive trajectories. Understanding variant-specific cognitive trajectories is clinically important for informed monitoring and identifying patients at risk for comorbid conditions. Here, we demonstrate a variant-specific normative chart for cognitive development for individuals with 22q11.2 deletion syndrome (22q11DS). We used IQ data from 1365 individuals with 22q11DS to construct variant-specific normative charts for cognitive development (Full Scale, Verbal, and Performance IQ). This allowed us to calculate Z-scores for each IQ datapoint. Then, we calculated the change between first and last available IQ assessments (delta Z-IQ-scores) for each individual with longitudinal IQ data (n = 708). We subsequently investigated whether using the variant-specific IQ-Z-scores would decrease required sample size to detect an effect with schizophrenia risk, as compared to standard IQ-scores. The mean Z-IQ-scores for FSIQ, VIQ, and PIQ were close to 0, indicating that participants had IQ-scores as predicted by the normative chart. The mean delta-Z-IQscores were equally close to 0, demonstrating a good fit of the normative chart and indicating that, as a group, individuals with 22q11DS show a decline in IQ-scores as they grow into adulthood. Using variant-specific IQ-Z-scores resulted in 30% decrease of required sample size, as compared to the standard IQ-based approach, to detect the association between IQ-decline and schizophrenia (p < 0.01). Our findings suggest that using variant-specific normative IQ data significantly reduces required sample size in a research context, and may facilitate a more clinically informative interpretation of IQ data. This approach allows identification of individuals that deviate from their expected, variant-specific, trajectory. This group may be at increased risk for comorbid conditions, such as schizophrenia in the case of 22q11DS.

Language Profiles of School-Aged Children with 22q11.2 Copy Number Variants

“…Comparisons to the normative sample confirmed that children with 22q11.2 CNVs have statistically significantly lower language scores in relation to typically developing peers, which is in accordance with results based on parental reports [ 13 ]. In addition, a shift of approximately −2 SD in the 22q11.2DS group is consistent with findings on their cognitive profiles in previous studies [ 53 , 54 , 55 , 56 ]. We found a shift of approximately −1.5 SD in the 22q11.2Dup group, which is at the lower end of the range of their cognitive capabilities based on previous studies.…”

Untargeted metabolic analysis in dried blood spots reveals metabolic signature in 22q11.2 deletion syndrome

“…The distribution of IQ scores, subdivided in full scale IQ (mean = 66.1, SD ± 10.4), verbal IQ (mean = 72.3, SD ± 12.4) and performance IQ (mean = 68.5, SD ± 11.2) was slightly skewed to the left compared to the normal distribution representative of 22q11.2DS patients as a whole [ 33 , 34 ] (Supplementary Fig. 2 ).…”

A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome

“…Here, again, findings in 22q11DS may provide helpful guidance for our understanding of the mechanisms underpinning these same phenomena in the context of other genetic variants. As discussed here, these likely include genetic variation in the rest of the genome, encompassing the modifying impact of both rare and common variants [98,99], environmental effects, and variation resulting from stochastic events during brain development. Animal models of 22q11DS have indeed shown that genetic background, as well as environmental and stochastic developmental effects modulate phenotypic expression and have pleiotropic effects [40,109,[166][167][168].…”

“…22q11DS, with an average of 70, is shifted approximately 30 points (or 2 standard deviations) to the left compared to the general population [99]. Similarly, while the penetrance of SSD and ASD diagnoses in 22q11DS is 25% and 10-40%, respectively, various studies have observed that the proportions of individuals with subclinical manifestations of both conditions are substantially higher [107,125].…”

“…For SSD, the picture is somewhat different: Both low (baseline) IQ and a decline in cognitive functioning have been associated with increased risk of SSD in individuals with 22q11DS, with the strongest effect size for a decline in Verbal IQ [3,99,100], largely converging with findings for idiopathic schizophrenia [101][102][103]. Thus, while cognitive decline and SSD were initially conceptualized as independent (pleiotropic) phenotypes in 22q11DS [11,104], substantial evidence has accumulated that these phenotypes are at least partly associated and may represent different developmental stages of the same disease process [99,100]. These findings in 22q11DS support the possibility of a similar association between early cognitive decline and schizophrenia proposed in the general population [105].…”