BackgroundPrior research has characterized neurodevelopmental phenotypes for Down syndrome (DS), but there is variability in age of milestone attainment and limited identification of early predictors of developmental trajectories. Additionally, less is known about receipt of education and services in relation to development.ObjectiveThis study describes the delivery of education and therapies in the setting of general developmental and behavioral needs in a large clinical cohort of children with DS seen in a specialized Down Syndrome Program (DSP).MethodThe clinically collected data included 814 patients with DS who were seen at a specialty DSP at a large, tertiary pediatric care center from March 2018 to January 2023. Data were collected through caregiver-and clinician-reported history at clinical visits to the program. Descriptive frequencies were utilized to describe participant demographics, skills and behaviors, and receipt of services, across age groups in childhood.ResultsDelays were present across all developmental domains; in particular delays in language, communication, and academic skills, and behavioral challenges were commonly reported. Almost all children received Early Intervention (EI) services, and many young children received non-public therapies after completing EI. Older participants demonstrated more impairments than younger age groups, yet received services at lower rates, particularly behavioral and speech language interventions.ConclusionA snapshot of developmental skill attainment in individuals with DS is provided. Therapies to support the levels of need were reported at much lower frequencies than the level of need reported to target aspects of development and behavior. Several gaps in therapies and educational services were identified. There is an important need for tailoring supports, based on developmental level, to meet individual needs. These findings may help to inform policy change related to developmental and educational services for individuals with DS.

Background: Despite the existing research exploring caregiver burden in adult psychosis, few studies have examined the experience of providing care to children diagnosed with psychotic disorders (PDs) and those identified as having clinical high risk for psychosis (CHR-P). Objective: This study measured the level of burden in caregivers of children with PD and CHR-P and examined associated risk factors, including social support, caregiver-child relationship, severity of illness, and frequency of psychiatric hospitalizations. Methods: A total of 56 caregivers completed validated measures and provided demographic information. Measures included the Zarit Burden Interview, the Multidimensional Scale of Perceived Social Support, the Behavior Assessment System for Children, Third Edition, Parenting Relationship Questionnaire-Child and Adolescent Form (BASC-3 PRQ-CA), and the Clinical Global Impression-Severity scale. Results: The majority of caregivers were women (86%), mothers (84%), White (63%), married (66%), working full-time (50%), college-educated (79%), and whose mean age was 45.7 years (SD = 8.09). Nearly half of the caregivers (45%) reported a high level of caregiver burden, 39% rated their burden in the mild to moderate range, and 16% reported little to no burden. There was no significant difference in mean burden between PD and CHR-P groups. Higher caregiver burden was associated with lower levels of social support (r = -.408, p = .002), lower levels of parenting confidence (r = -.514, p < .001), higher levels of relational frustration (r = .612, p < .001), and higher severity of illness (r = .316 p = .025). Conclusions: These findings underscore the critical unmet need for support for caregivers of children with PD and CHR-P. Applications to clinical practice are discussed.

Background Early onset psychosis (EOP) frequently presents with a severe clinical phenotype and poor long-term prognosis. Clinical experience suggests that individuals with EOP have abnormal pain and somatosensory processing, yet relative to adult-onset psychosis, pain and somatic sensory processing in EOP have rarely been studied. Methods The history of two characteristic patients is described to illustrate clinical presentations of pain in EOP patients. Furthermore, 31 patients with EOP were studied with self-reported questionnaires informing on pain severity, pain catastrophizing, central sensitization, and somatization. Structured clinical interviews were administered to confirm Diagnostic and Statistical Manual of Mental Disorders-5 EOP diagnosis and the patient’s dimensions of psychopathology were measured by the Brief Psychiatric Rating Scale (BPRS). Results Out of 31 EOP patients, 22 reported distressing pain, where higher pain severity corresponded with greater BPRS total and affectivity and resistance subscale scores. The degree of psychopathology was associated (N=31; p < 0.05, FDR-corrected) with the magnitude of pain catastrophizing, central sensitization, and somatization. Multivariate analysis revealed relationships (N=31; p < 0.05, FDR-corrected) between BPRS subscale (negative symptoms and activation) scores with somatization severity. The observed associations occurred independent of antipsychotic medication usage as quantified by chlorpromazine equivalent doses. Conclusions Pain and somatosensory symptoms could be a frequent cause of distress in patients with EOP and their severity associated with the degree of psychopathology. Future studies should determine if treating pain and somatic symptoms in EOP patients can lead to better control of psychosis as well as improve quality of life.

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:Families of children with neurodevelopmental disorders have developmental, behavioral, and social-emotional needs that affect quality of life (QoL). This study assesses the validity and utility of a caregiver QoL measure; characterizes QoL in families with children with Down syndrome (DS), autism spectrum disorder (ASD), and a dual diagnosis of DS and ASD (DS + ASD); and compares and explores differences in QoL based on diagnosis.METHODS:Caregivers of children and adolescents with ASD (n = 610) and DS (n = 177) completed the Pediatric Quality of Life Inventory Family Impact Module 2.0, yielding overall, parent functioning, family functioning, and subscale scores, and a Parent Global Impression (PGI) rating. An ASD cohort (n = 177) was sex matched to the DS cohort (n = 177) to mitigate potential sex bias. Additional analyses compared these groups with children and adolescents with DS + ASD (n = 37).RESULTS:Analyses showed that the Pediatric Quality of Life Inventory was valid and reliable in DS, ASD, and DS + ASD populations. No differences were reported in PGI ratings among groups. Caregivers in the DS group demonstrated higher QoL and family functioning compared with the ASD and DS + ASD groups. The DS group reported significantly better Emotional Functioning and Communication and less Worry than the ASD group. Compared with the ASD group, caregivers of the DS + ASD group indicated more concerns with Physical Functioning. Notably, the DS + ASD group had significantly lower levels of QoL than the DS group in nearly all caregiver functioning domains.CONCLUSION:This study highlights differences in QoL within and between neurodevelopmental disorder groups, which may help identify families requiring additional support, advocacy, and community engagement.

American Journal of Medical Genetics Part AVolume 191, Issue 5 p. 1470-1473 RESEARCH LETTER Response to Letter to the Editor by Palffy and Ghaziuddin Stephanie L. Santoro, Corresponding Author Stephanie L. Santoro [email protected] orcid.org/0000-0002-4172-0288 Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA Correspondence Stephanie L. Santoro, Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, 125 Nashua St., Suite 821, Boston, MA 02114, USA. Email: [email protected]Search for more papers by this authorNicole T. Baumer, Nicole T. Baumer orcid.org/0000-0003-2170-3058 Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA Boston Children's Hospital Down Syndrome Program, Boston Children's Hospital, Boston, Massachusetts, USASearch for more papers by this authorMichelle Cornacchia, Michelle Cornacchia Geisinger Health System, Danville, Pennsylvania, USASearch for more papers by this authorCatherine Franklin, Catherine Franklin Mater Research Institute-University of Queensland, The University of Queensland, South Brisbane, AustraliaSearch for more papers by this authorSarah J. Hart, Sarah J. Hart orcid.org/0000-0003-0974-3209 Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USASearch for more papers by this authorKelsey Haugen, Kelsey Haugen Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorMargaret A. Hojlo, Margaret A. Hojlo orcid.org/0000-0003-3757-9776 Boston Children's Hospital Down Syndrome Program, Boston Children's Hospital, Boston, Massachusetts, USASearch for more papers by this authorNora Horick, Nora Horick Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorPriya S. Kishnani, Priya S. Kishnani Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USASearch for more papers by this authorKavita Krell, Kavita Krell orcid.org/0000-0002-7905-871X Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorAndrew McCormick, Andrew McCormick Down Syndrome Center of Western Pennsylvania, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USASearch for more papers by this authorAnna L. Milliken, Anna L. Milliken Boston Children's Hospital Down Syndrome Program, Boston Children's Hospital, Boston, Massachusetts, USASearch for more papers by this authorNicolas M. Oreskovic, Nicolas M. Oreskovic orcid.org/0000-0001-8702-8636 Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorKatherine G. Pawlowski, Katherine G. Pawlowski Boston Children's Hospital Down Syndrome Program, Boston Children's Hospital, Boston, Massachusetts, USASearch for more papers by this authorSabrina Sargado, Sabrina Sargado Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA Boston Children's Hospital Down Syndrome Program, Boston Children's Hospital, Boston, Massachusetts, USASearch for more papers by this authorAmy Torres, Amy Torres Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorDiletta Valentini, Diletta Valentini Pediatric and Infectious Disease Unit, Bambino Gesù Children's Hospital, Rome, ItalySearch for more papers by this authorKishore Vellody, Kishore Vellody orcid.org/0000-0002-2116-6486 Down Syndrome Center of Western Pennsylvania, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USASearch for more papers by this authorBrian G. Skotko, Brian G. Skotko orcid.org/0000-0002-5232-9882 Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this author Stephanie L. Santoro, Corresponding Author Stephanie L. Santoro [email protected] orcid.org/0000-0002-4172-0288 Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA Correspondence Stephanie L. Santoro, Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, 125 Nashua St., Suite 821, Boston, MA 02114, USA. Email: [email protected]Search for more papers by this authorNicole T. Baumer, Nicole T. Baumer orcid.org/0000-0003-2170-3058 Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA Boston Children's Hospital Down Syndrome Program, Boston Children's Hospital, Boston, Massachusetts, USASearch for more papers by this authorMichelle Cornacchia, Michelle Cornacchia Geisinger Health System, Danville, Pennsylvania, USASearch for more papers by this authorCatherine Franklin, Catherine Franklin Mater Research Institute-University of Queensland, The University of Queensland, South Brisbane, AustraliaSearch for more papers by this authorSarah J. Hart, Sarah J. Hart orcid.org/0000-0003-0974-3209 Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USASearch for more papers by this authorKelsey Haugen, Kelsey Haugen Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorMargaret A. Hojlo, Margaret A. Hojlo orcid.org/0000-0003-3757-9776 Boston Children's Hospital Down Syndrome Program, Boston Children's Hospital, Boston, Massachusetts, USASearch for more papers by this authorNora Horick, Nora Horick Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorPriya S. Kishnani, Priya S. Kishnani Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USASearch for more papers by this authorKavita Krell, Kavita Krell orcid.org/0000-0002-7905-871X Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorAndrew McCormick, Andrew McCormick Down Syndrome Center of Western Pennsylvania, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USASearch for more papers by this authorAnna L. Milliken, Anna L. Milliken Boston Children's Hospital Down Syndrome Program, Boston Children's Hospital, Boston, Massachusetts, USASearch for more papers by this authorNicolas M. Oreskovic, Nicolas M. Oreskovic orcid.org/0000-0001-8702-8636 Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorKatherine G. Pawlowski, Katherine G. Pawlowski Boston Children's Hospital Down Syndrome Program, Boston Children's Hospital, Boston, Massachusetts, USASearch for more papers by this authorSabrina Sargado, Sabrina Sargado Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA Boston Children's Hospital Down Syndrome Program, Boston Children's Hospital, Boston, Massachusetts, USASearch for more papers by this authorAmy Torres, Amy Torres Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorDiletta Valentini, Diletta Valentini Pediatric and Infectious Disease Unit, Bambino Gesù Children's Hospital, Rome, ItalySearch for more papers by this authorKishore Vellody, Kishore Vellody orcid.org/0000-0002-2116-6486 Down Syndrome Center of Western Pennsylvania, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USASearch for more papers by this authorBrian G. Skotko, Brian G. Skotko orcid.org/0000-0002-5232-9882 Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this author First published: 06 January 2023 https://doi.org/10.1002/ajmg.a.63116Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL REFERENCES Anthonio, G., Malik, F., Ghomeshi, A., Lopez, O., & Gralnik, L. (2022). 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Individuals with Down syndrome (DS) experience a range of medical and neurodevelopmental conditions, necessitating systematic study of their occurrence and impact on neurodevelopmental outcomes. We describe the prevalence and relationships of medical, neurodevelopmental (ND), and mental health (MH) conditions in children with DS. We created a prospective clinical database of individuals with DS, integrated into the workflow of a specialty Down Syndrome Program at a specialty pediatric referral hospital. Conditions were collected through caregiver- and clinician report at clinical visits (N = 599). We calculated frequencies of medical, ND, and MH conditions and then assessed the relationship between medical, ND, and MH conditions using frequencies and comparative statistics. The most frequent co-occurring conditions were vision (72.5%), ear/hearing (71.0%), gastrointestinal (61.3%), respiratory (45.6%), and feeding (33.6%) problems, with variation in frequency by age. ND and MH conditions were reported in one quarter, most commonly autism spectrum disorder and attention-deficit/hyperactivity disorder. Those with ND and MH conditions had greater frequency of medical conditions, with highest rates of vision, ear/hearing, and gastrointestinal issues, and CHD. Systematically collected clinical data in a large cohort of children with DS reveals high prevalence of several co-occurring medical, ND, and MH conditions. Clinical care requires an understanding of the complex relationship between medical conditions and neurodevelopment.

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.

Objective: To describe the distribution of expressive language abilities of individuals with Down syndrome (DS) in a clinical sample and characterize demographic, environmental, and medical factors associated with varying expressive language profiles. Methods: Cross-sectional analysis was completed on a sample of 345 individuals with DS between the ages of 4 and 22 years who were enrolled into a longitudinal clinical database between March 2018 and August 2021. Expressive language-related items on a standardized caregiver-reported questionnaire assessing domains of functioning in neurodevelopmental disorders were used to conduct latent variable modeling and determine caregiver-reported expressive language (CREL) classes across the sample. Linear regression was used to explore associations between CREL classes and predictor variables. Results: Latent variable modeling revealed 3 distinct classes of CREL abilities representing higher, middle, and lower CREL. Individuals in the lower CREL class were more likely to be female, to use sign language or visual communication systems, have reduced pronunciation, attend private or residential school, and to be in a substantially separate classroom. Membership was not predicted by complex medical histories or co-occurring neurodevelopmental diagnoses. Conclusion: Caregiver-reported expressive language abilities in a cohort of individuals with DS were variable, with most of the individuals belonging to higher or middle CREL classes, relative to one another. Additional studies are indicated to understand factors that predict higher expressive language ability and explore how to direct services to individuals who are at risk of more profound language delays.

BACKGROUND:While past research has underscored the benefits of physical activity for people with Down syndrome (DS), exercise programming that is customised to and/or accessible for children and adolescents with DS is limited. The objectives of this pilot were to (1) develop and refine an engaging exercise programme for adolescents with DS, called DSFit; (2) assess feasibility over the course of two pilot iterations; and (3) examine participant and parent feedback regarding exercise priorities and the DSFit exercise programme.METHOD:Participants were 12 unique adolescents (ages 11-17 years) with DS. Both pilot iterations of the programme consisted of weekly group exercise sessions and home exercises to complete between sessions. Physical fitness and mood/behaviour were assessed at baseline and at the end of the intervention. Parent and child goal-setting and feedback surveys were collected before and immediately after the intervention, and a 2-month follow-up assessed physical activity and exercise attitudes. Quality improvement methodology and participant/parent feedback were used to modify the second iteration to better meet the needs of our study population. Changes included an expanded age range, modified physical assessments, decreased burden of questionnaires, and video-recorded group sessions for at-home practice.RESULTS:Physical fitness evaluation of core/trunk strength and stability, lower- and upper-body strength, balance, flexibility, and walking was feasible, and the majority of participants in both pilot iterations improved in at least one category of physical assessment between baseline and end of intervention. Assessment of symptoms of anxiety, depression and behavioural concerns was also feasible and results showed slight improvements in some participants. Both parent and participant feedback indicated that participants enjoyed the programme and appreciated the opportunity to start developing sustainable exercise habits.CONCLUSIONS:A group exercise programme with supported at-home components is feasible for adolescents with DS. Future iterations will continue to examine programme efficacy with improved fitness testing and larger sample sizes. Strategies to increase at-home compliance, such as virtual sessions and parent/guardian-guided physical fitness assessments, will also be incorporated.

Objective: Unexplained regression in Down syndrome (URDS) involves a loss of acquired skills resulting in functional deterioration. Despite extensive workup and treatment, few individuals regain baseline function. This study aimed to understand the role of psychosocial stressors in URDS. Methods: We describe psychosocial stressors in 14 cases of URDS. Specifically, we examined psychosocial stressors in the context of presentation and clinical symptoms. We also examined co-occurring neurodevelopmental disorders and medical and mental health conditions. Results: All individuals experienced psychosocial stressors within one year of diagnosis of URDS. The most common psychosocial stressors were moving to a new home or school. Conclusion: Psychosocial stressors are commonly reported preceding URDS. Knowledge about psychosocial stressors' impact may lead to preventive interventions, improved monitoring, and earlier diagnosis. Future research should focus on understanding psychosocial stressors to help identify individuals at risk for URDS and contribute to treatment.

Research to guide clinicians in the management of the devastating regression which can affect adolescents and young adults with Down syndrome is limited. A multi-site, international, longitudinal cohort of individuals with a clinical diagnosis of Unexplained Regression in Down syndrome (URDS) was collated through seven Down syndrome clinics. Tiered medical evaluation, a 28-item core symptom list, and interim management are described naturalistically. Improvement-defined by the percentage of baseline function on a Parent-reported Functional Score, overall improvement in symptoms on a Clinician-administered Functional Assessment, or report of management type being associated with improvement-was analyzed. Improvement rates using ECT, IVIG, and others were compared. Across seven clinics, 51 patients with URDS had regression at age 17.6 years, on average, and showed an average 14.1 out of 28 symptoms. Longitudinal improvement in function was achieved in many patients and the medical management, types of treatment, and their impact on function are described. Management with intravenous immunoglobulin (IVIG) was significantly associated with higher rate of improvement in symptoms at the next visit (p = 0.001). Our longitudinal data demonstrates that URDS is treatable, with various forms of clinical management and has a variable course. The data suggests that IVIG may be an effective treatment in some individuals. Our description of the management approaches used in this cohort lays the groundwork for future research, such as development of standardized objective outcome measure and creation of a clinical practice guideline for URDS.

Objective: Copy number variants (CNVs) are strongly associated with neurodevelopmental and psychotic disorders. Early-onset psychosis (EOP), where symptoms appear before 18 years of age, is thought to be more strongly influenced by genetic factors than adult-onset psychotic disorders. However, the prevalence and effect of CNVs in EOP is unclear. Methods: The authors documented the prevalence of recurrent CNVs and the functional impact of deletions and duplications genome-wide in 137 children and adolescents with EOP compared with 5,540 individuals with autism spectrum disorder (ASD) and 16,504 population control subjects. Specifically, the frequency of 47 recurrent CNVs previously associated with neurodevelopmental and neuropsychiatric illnesses in each cohort were compared. Next, CNV risk scores (CRSs), indices reflecting the dosage sensitivity for any gene across the genome that is encapsulated in a deletion or duplication separately, were compared between groups. Results: The prevalence of recurrent CNVs was significantly higher in the EOP group than in the ASD (odds ratio=2.30) and control (odds ratio=5.06) groups. However, the difference between the EOP and ASD groups was attenuated when EOP participants with co-occurring ASD were excluded. CRS was significantly higher in the EOP group compared with the control group for both deletions (odds ratio=1.30) and duplications (odds ratio=1.09). In contrast, the EOP and ASD groups did not differ significantly in terms of CRS. Conclusions: Given the high frequency of recurrent CNVs in the EOP group and comparable CRSs in the EOP and ASD groups, the findings suggest that all children and adolescents with a psychotic diagnosis should undergo genetic screening, as is recommended in ASD.

ABSTRACT: 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.

Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning over the course of a year and subsequently presented with catatonia, auditory and visual hallucinations, paranoia, aggression, mood dysregulation, and disorganized thoughts. Exome sequencing revealed a stop-gain mutation in RCL1 (NM_005772.4:c.370 C > T, p.Gln124Ter), encoding an RNA 3′-terminal phosphate cyclase-like protein that is highly conserved across eukaryotic species. Subsequent investigations across two academic medical centers identified eleven additional cases of RCL1 copy number variations (CNVs) with varying neurodevelopmental or psychiatric phenotypes. These findings suggest that dosage variation of RCL1 contributes to a range of neurological and clinical phenotypes.

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.

22 Despite the known heritable nature of autism spectrum disorder (ASD), studies have primarily 23 identified risk genes with de novo variants (DNVs). To capture the full spectrum of ASD genetic 24 risk, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 25 ASD cases, including 35,130 new cases recruited online by SPARK. In the first stage, we analyzed 26 19,843 cases with one or both biological parents and found that known ASD or 27 neurodevelopmental disorder (NDD) risk genes explain nearly 70% of the genetic burden 28 conferred by DNVs. In contrast, less than 20% of genetic risk conferred by rare inherited loss-of29 function (LoF) variants are explained by known ASD/NDD genes. We selected 404 genes based 30 on the first stage of analysis and performed a meta-analysis with an additional 22,764 cases and 31 236,000 population controls. We identified 60 genes with exome-wide significance (p < 2.5e-6), 32 including five new risk genes (NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2). The association of 33 NAV3 with ASD risk is entirely driven by rare inherited LoFs variants, with an average relative 34 risk of 4, consistent with moderate effect. ASD individuals with LoF variants in the four 35 moderate risk genes (NAV3, ITSN1, SCAF1, and HNRNPUL2, n = 95) have less cognitive 36 impairment compared to 129 ASD individuals with LoF variants in well-established, highly 37 penetrant ASD risk genes (CHD8, SCN2A, ADNP, FOXP1, SHANK3) (59% vs. 88%, p= 1.9e-06) . 38 These findings will guide future gene discovery efforts and suggest that much larger numbers of 39 ASD cases and controls are needed to identify additional genes that confer moderate risk of 40 ASD through rare, inherited variants. 41 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted October 11, 2021. ; https://doi.org/10.1101/2021.10.08.21264256 doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Very early-onset psychosis (VEOP) is defined as the onset of psychotic symptoms before 13 years of age and is considered to be a more severe form of the more typical adolescent/adult-onset psychosis. Therefore, we hypothesize that VEOP will have a higher rate of rare genetic mutations. The objective of this study is to compare the genetic burden of schizophrenia-related copy number variants (CNVs) in a clinically referred VEOP cohort to that of schizophrenia variants that have been found in a Psychiatric Genomics Consortium adult-onset psychosis cohort.