A normative chart for cognitive development in a genetically selected population.

Area of Science:

• Neurogenetics
• Developmental Psychology
• Clinical Genetics

Background:

• Pathogenic genetic variants can alter neurodevelopment and cognitive trajectories.
• Understanding these variant-specific trajectories is crucial for clinical monitoring and identifying comorbid condition risks.
• 22q11.2 deletion syndrome (22q11DS) is associated with neurodevelopmental variations.

Purpose of the Study:

• To create a variant-specific normative chart for cognitive development in individuals with 22q11DS.
• To assess the utility of this chart in reducing sample size for genetic association studies.
• To provide a tool for more clinically informative interpretation of IQ data and identification of at-risk individuals.

Main Methods:

• Constructed variant-specific normative charts for Full Scale, Verbal, and Performance IQ using data from 1365 individuals with 22q11DS.
• Calculated Z-scores for individual IQ data points and delta Z-IQ-scores from longitudinal data (n=708).
• Compared the required sample size to detect the association between IQ decline and schizophrenia risk using variant-specific versus standard IQ scores.

Main Results:

• The normative chart demonstrated a good fit, with mean Z-IQ and delta Z-IQ scores near 0.
• A group decline in IQ scores was observed in individuals with 22q11DS from childhood to adulthood.
• Utilizing variant-specific IQ-Z-scores reduced the required sample size by 30% for detecting the IQ decline-schizophrenia association (p<0.01).

Conclusions:

• Variant-specific normative IQ data significantly decrease the required sample size in research settings.
• This approach enhances the clinical interpretability of IQ data for individuals with 22q11DS.
• It facilitates the identification of individuals deviating from their expected trajectory, potentially indicating increased risk for comorbid conditions like schizophrenia.