Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5

Background and Objectives KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants.Methods We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details.Results We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death.Discussion We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.</p

At-Home use of App-Based Mindfulness for Children: A Randomized Active-Controlled Trial

Abstract Objectives School-based mindfulness interventions in children have shown benefits to child well-being. Here, we investigated the effectiveness of a remote, app-based mindfulness intervention for promoting well-being in children. Method We conducted a randomized controlled trial (RCT) with two control groups to examine the effects of an 8-week mindfulness intervention in U.S. children ages 8–10. We compared pre-post effects between a mindfulness intervention using the Inner Explorer app, and two audiobook control interventions. The 279 children who participated in the interventions were assessed on self-report measures of anxiety and depression symptoms, perceived stress and trait mindfulness and we also collected parental reports. Results Over 80% of children completed the intervention in each condition. There was evidence for reduced self-perceived stress in children and reduced negative affect in children by parental reports using the mindfulness app, but no significant reduction for anxiety or depression symptoms. In general, between-group effect sizes were small (d < 0.45). Regular use, defined as at least 30 days of mindfulness practice within the study period, was associated with reduced child negative affect by parental reports, as well as reduced parental stress and child self-perceived stress. Conclusions These findings suggest that home use of a mindfulness app in young children can have a positive impact on children’s emotional well-being if the app is used regularly, specifically for at least 30 days in the 8-week study period. Strategies aimed at promoting regular use of the mindfulness app at home could lead to even better outcomes for children. Preregistration Preregistered on OSF at https://osf.io/23va

Implementing Remote Developmental Research: A Case Study of a Randomized Controlled Trial Language Intervention During COVID-19

Intervention studies with developmental samples are difficult to implement, in particular when targeting demographically diverse communities. Online studies have the potential to examine the efficacy of highly scalable interventions aimed at enhancing development, and to address some of the barriers faced by underrepresented communities for participating in developmental research. During the COVID-19 pandemic, we executed a fully remote randomized controlled trial (RCT) language intervention with third and fourth grade students (N = 255; age range 8.19–10.72 years, mean = 9.41, SD = 0.52) from diverse backgrounds across the United States. Using this as a case study, we discuss both challenges and solutions to conducting an intensive online intervention through the various phases of the study, including recruitment, data collection, and fidelity of intervention implementation. We provide comprehensive suggestions and takeaways, and conclude by summarizing some important tradeoffs for researchers interested in carrying out such studies.National Science Foundation (Grant 1745302)theNational Institutes of Health (Grant F32-HD100064