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.

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.

Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 from SPARK) and 31,052 DD trios independently and also combined as broader neurodevelopmental disorders (NDDs) using three models. We identify 615 NDD candidate genes (false discovery rate [FDR] < 0.05) supported by ≥1 models, including 138 reaching Bonferroni exome-wide significance ( P < 3.64e–7) in all models. The genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes that show mutational bias, including enrichments for missense ( n = 41) or truncating ( n = 12) DNVs. We also find 10 genes with evidence of male- or female-bias enrichment, including 4 X chromosome genes with significant female burden ( DDX3X , MECP2 , WDR45 , and HDAC8) . This large-scale integrative analysis identifies candidates and functional subsets of NDD genes.

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.