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-IQ-scores 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.
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The authors wish to thank all participants and their families for their participation in this study.
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Authors AMF, JASV, and EJB had full access to the data and take responsibility for the accuracy of the data and analyses. Authors JASV and EJB contributed equally to this manuscript. All authors, including the members of the 22q11DS International Consortium on Brain and Behavior, contributed important intellectual content and reviewed the manuscript. A complete list of contributing authors, including the members of the 22q11DS International Consortium on Brain and Behavior, is listed in Supplementary Materials 2.
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Fiksinski, A.M., Bearden, C.E., Bassett, A.S. et al. A normative chart for cognitive development in a genetically selected population. Neuropsychopharmacol. 47, 1379–1386 (2022). https://doi.org/10.1038/s41386-021-00988-6
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DOI: https://doi.org/10.1038/s41386-021-00988-6
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