Background: 16p13.11 microduplication syndrome has a variable presentation and is characterized primarily by neurodevelopmental and physical phenotypes resulting from copy number variation at chromosome 16p13.11. Given its variability, there may be features that have not yet been reported. The goal of this study was to use a patient “self-phenotyping” survey to collect data directly from patients to further characterize the phenotypes of 16p13.11 microduplication syndrome. Objective: This study aimed to (1) discover self-identified phenotypes in 16p13.11 microduplication syndrome that have been underrepresented in the scientific literature and (2) demonstrate that self-phenotyping tools are valuable sources of data for the medical and scientific communities. Methods: As part of a large study to compare and evaluate patient self-phenotyping surveys, an online survey tool, Phenotypr, was developed for patients with rare disorders to self-report phenotypes. Participants with 16p13.11 microduplication syndrome were recruited through the Boston Children's Hospital 16p13.11 Registry. Either the caregiver, parent, or legal guardian of an affected child or the affected person (if aged 18 years or above) completed the survey. Results were securely transferred to a Research Electronic Data Capture database and aggregated for analysis. Results: A total of 19 participants enrolled in the study. Notably, among the 19 participants, aggression and anxiety were mentioned by 3 (16%) and 4 (21%) participants, respectively, which is an increase over the numbers in previously published literature. Additionally, among the 19 participants, 3 (16%) had asthma and 2 (11%) had other immunological disorders, both of which have not been previously described in the syndrome. Conclusions: Several phenotypes might be underrepresented in the previous 16p13.11 microduplication literature, and new possible phenotypes have been identified. Whenever possible, patients should continue to be referenced as a source of complete phenotyping data on their condition. Self-phenotyping may lead to a better understanding of the prevalence of phenotypes in genetic disorders and may identify previously unreported phenotypes.

Background: Children and adolescents with early-onset psychosis (EOP) have more rare genetic variants than individuals with adult-onset forms of the illness, implying that fewer EOP participants are needed for genetic discovery. The Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) study predicted that 10 genes with ultra-rare variation were linked to adult-onset schizophrenia. We hypothesized that rare variants predicted “High” and “Moderate” by the Variant Effect Predictor Algorithm (abbreviated as VEPHMI) in these 10 genes would be enriched in our EOP cohort. Methods: We compared rare VEPHMI variants in individuals with EOP (N = 34) with race- and sex-matched controls (N = 34) using the sequence kernel association test (SKAT). Results: GRIN2A variants were significantly increased in the EOP cohort (p = 0.004), with seven individuals (20% of the EOP cohort) carrying a rare VEPHMI variant. The EOP cohort was then compared to three additional control cohorts. GRIN2A variants were significantly increased in the EOP cohort for two of the additional control sets (p = 0.02 and p = 0.02), and trending towards significance for the third (p = 0.06). Conclusion: Despite a small sample size, GRIN2A VEPHMI variant burden was increased in a cohort of individuals with EOP in comparison to controls. GRIN2A variants have been associated with a range of neuropsychiatric disorders including adult-onset psychotic spectrum disorder and childhood-onset schizophrenia. This study supports the role of GRIN2A in EOP and emphasizes its role in neuropsychiatric disorders.

Down syndrome (DS) is a complex condition associated with multiple medical, developmental, and behavioral concerns. A prospective, longitudinal clinical database was integrated into a specialty Down Syndrome Program, with the goals of better understanding the incidence, course, and impact of co-occurring medical, neurodevelopmental, and mental health conditions in DS. We describe the process of developing the database, including a systematic approach to data collection and database infrastructure, and report on feasibility, challenges, and solutions of initial implementation. Between March 2018 and November 2021, data from 842 patients (ages 4.8 months to 26 years) was collected. Challenges included caregiver form completion as well as time and personnel required for successful implementation. With full integration into clinical visit flow, the database proved to be feasible. The database enables identification of patterns of development and health throughout the lifespan and it facilitates future data sharing and collaborative research to advance care.

Objective: As understanding of the neurobiological basis of cognitive impairment in Down syndrome (DS) advances and new pharmaceutical interventions targeting neurodevelopment become available, an in-depth understanding of the family perspective is essential to inform research efforts. A mixed methods study was conducted with parents of individuals with DS to learn about attitudes toward pharmacological interventions to enhance cognition, participation in clinical research trials in DS, and the relationship between child/family-specific factors and parent attitudes. Method: Parents completed an online survey (N = 37) assessing family/child sociodemographic factors and to capture thoughts on cognitive enhancement and participation in clinical drug trials. A subset of interested parents participated in a follow-up phone interview (N = 21) or focus group (N = 3; 1 FG). Double-blind thematic analysis was used to analyze qualitative data. Results: Parents' attitudes toward improving cognition, reversing intellectual disability, and participation in clinical trials correlated with each other and were informed by specific parent and child factors (e.g., child attention-deficit hyperactivity disorder/behavioral diagnosis and parent education). Qualitative themes included advantages, disadvantages, and ethical implications of enhancing cognition. In addition, themes emerged regarding the need to understand the mechanism and potential side effects of experimental drugs, logistical factors relating to willingness to participate in clinical trials, and the evolution of parents' attitudes over time. Conclusion: The findings highlight the complexity of issues and implications of clinical trials for enhancing cognition in DS. Child-specific factors, logistical and safety considerations, and personal belief systems all inform parent attitudes and decision making. The findings reflect the importance of incorporating parent perspectives and values in research direction and design.