Deep psychophysiological phenotyping of adolescents and adults with 22q11.2 deletion syndrome: a multilevel approach to defining core disease processes.

Researchers are studying 22q11.2 deletion syndrome, a genetic condition that can cause heart problems, immune issues, developmental delays, autism, and psychiatric conditions like schizophrenia. They're using brain wave tests, reflex measurements, and laboratory studies of brain cells to understand how the genetic change affects brain function and behavior. The study includes people aged 16-60 and aims to better understand why some people with this condition develop certain symptoms while others don't.

This study protocol describes a comprehensive research approach to understand 22q11.2 deletion syndrome (22q11.2DS), a genetic condition affecting 1 in 2000-6000 births. The research employs 'deep phenotyping' using psychophysiological assessments (EEG, evoked potentials, acoustic startle) combined with stem cell-derived neuronal studies to examine the biological mechanisms underlying psychiatric symptoms, particularly psychotic disorders. The study recruits individuals aged 16-60 with 22q11.2DS and controls, conducting extensive clinical assessments including autism spectrum and ADHD symptom measures. The central hypothesis is that abnormal neural processing correlates with psychophysiological changes and drives clinical symptoms.

This multilevel approach aims to identify core disease processes and could inform treatment development for this complex genetic syndrome.

While this protocol paper doesn't provide clinical outcomes, the comprehensive assessment approach described could advance understanding of 22q11.2DS mechanisms and inform future treatment strategies. The inclusion of autism spectrum assessments acknowledges the overlap between 22q11.2DS and autism, potentially contributing to better diagnostic and therapeutic approaches for individuals with this genetic syndrome.

This is a study protocol paper describing planned research methodology rather than presenting actual results or findings. No sample size, participant characteristics, or outcome data are reported as data collection is ongoing.

22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal interstitial-deletion disorder, occurring in approximately 1 in 2000 to 6000 live births. Affected individuals exhibit variable clinical phenotypes that can include velopharyngeal anomalies, heart defects, T-cell-related immune deficits, dysmorphic facial features, neurodevelopmental disorders, including autism, early cognitive decline, schizophrenia, and other psychiatric disorders. Developing comprehensive treatments for 22q11.2DS requires an understanding of both the psychophysiological and neural mechanisms driving clinical outcomes. Our project probes the core psychophysiological abnormalities of 22q11.2DS in parallel with molecular studies of stem cell-derived neurons to unravel the basic mechanisms and pathophysiology of 22q11.2-related psychiatric disorders, with a primary focus on psychotic disorders.

Our study is guided by the central hypothesis that abnormal neural processing associates with psychophysiological processing and underlies clinical diagnosis and symptomatology. Here, we present the scientific background and justification for our study, sharing details of our study design and human data collection protocol. Our study is recruiting individuals with 22q11.2DS and healthy comparison subjects between the ages of 16 and 60 years. We are employing an extensive psychophysiological assessment battery (e.g., EEG, evoked potential measures, and acoustic startle) to assess fundamental sensory detection, attention, and reactivity.

To complement these unbiased measures of cognitive processing, we will develop stem-cell derived neurons and examine neuronal phenotypes relevant to neurotransmission. Clinical characterization of our 22q11.2DS and control participants relies on diagnostic and research domain criteria assessments, including standard Axis-I diagnostic and neurocognitive measures, following from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and the North American Prodrome Longitudinal Study (NAPLS) batteries. We are also collecting measures of autism spectrum (ASD) and attention deficit/hyperactivity disorder (ADHD)-related symptoms. Studying 22q11.2DS in adolescence and adulthood via deep phenotyping across multiple clinical and biological domains may significantly increase our knowledge of its core disease processes.

Our manuscript describes our ongoing study's protocol in detail. These paradigms could be adapted by clinical researchers studying 22q11.2DS, other CNV/single gene disorders, or idiopathic psychiatric syndromes, as well as by basic researchers who plan to incorporate biobehavioral outcome measures into their studies of 22q11.2DS.