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Objective: To understand parents' of children with developmental and epileptic encephalopathies needs and preferences for psychological resources. Methods: Using a person-based approach, a multidisciplinary panel of clinician and researchers (n = 9) hosted a priority-setting workshop to 1) understand parents' needs and preferences for psychological resources and 2) to develop ‘guiding principles’ to inform a future suite of psychological resources. The multidisciplinary panel analysed the parent priority-setting workshop data, using a combination of thematic and lexical analysis. Results: Thematic analysis identified six key domains wherein parents (n = 8) prioritised a need for psychological resources to support adaptation to their child's genetic DEE diagnosis. Lexical analysis revealed that connection to diagnosis-specific resources provided a pathway to promote enhanced psychological adaptation, by reducing social isolation and reorienting parents towards feelings of hope. Combination of both analyses generated six thematic informed ‘guiding principles’. Conclusion: Codesigned psychological resources may help parents to cope with the unique and complex interplay of stressors associated with their child's DEE diagnosis and treatment. Our ‘guiding principles’ will be translated to inform a future suite of tailored psychological resources. Innovation: This study demonstrates an innovative codesign approach to inform tailored psychological resources for families of children with rare genetic conditions.

Introduction Developmental and epileptic encephalopathies (DEEs) are rare epilepsy conditions that collectively impact 1 in 2000 children. They are highly genetically heterogeneous, resulting in significant barriers to accurate and adequate information for caregivers. This can lead to increased distress and dissatisfaction with the healthcare system. To address this gap, we developed ‘GenE Compass’ to provide caregivers with the highest-quality possible, understandable and relevant information in response to specific questions about their child’s DEE. Using a mixed-method design, we will now pilot GenE Compass to evaluate the acceptability to caregivers and clinicians, feasibility and impact to caregivers.Methods and analysis We will recruit 88 caregivers (estimated final sample of 50 at follow-up) who have a child under 18 years of age with a suspected or confirmed DEE diagnosis. Following consent and a baseline questionnaire (questionnaire 1 (Q1)), participants will be able to submit questions to GenE Compass over a 3-month period. After 3 months, participants will complete a follow-up questionnaire (Q2) and an optional telephone interview to answer the research questions. Primary outcomes are acceptability of GenE Compass and feasibility of delivering the intervention (eg, cost of the intervention, number of questions submitted and time taken to respond to questions). Secondary outcomes include the impact of GenE Compass on caregivers’ quality of life, information searching behaviours, perceptions of their child’s illness and activation.Ethics and discussion The study protocol (V.2, dated 16 September 2021) has been approved by the Sydney Children’s Hospitals Network Human Research Ethics Committee (ETH11277). The results will be disseminated in peer-reviewed journals and at scientific conferences. A lay summary will be disseminated to all participants.Trial registration number ACTRN12621001544864.

Summary: Early infantile epileptic encephalopathies (EOEE) are a debilitating spectrum of disorders associated with cognitive impairments. We present a clinical report of a KCNT2 mutation in an EOEE patient. The de novo heterozygous variant Phe240Leu SLICK was identified by exome sequencing and confirmed by Sanger sequencing. Phe240Leu rSlick and hSLICK channels were electrophysiologically, heterologously characterized to reveal three significant alterations to channel function. First, [Cl−]i sensitivity was reversed in Phe240Leu channels. Second, predominantly K+-selective WT channels were made to favor Na+ over K+ by Phe240Leu. Third, and consequent to altered ion selectivity, Phe240Leu channels had larger inward conductance. Further, rSlick channels induced membrane hyperexcitability when expressed in primary neurons, resembling the cellular seizure phenotype. Taken together, our results confirm that Phe240Leu is a “change-of-function” KCNT2 mutation, demonstrating unusual altered selectivity in KNa channels. These findings establish pathogenicity of the Phe240Leu KCNT2 mutation in the reported EOEE patient. : Gururaj et al. report a KCNT2 mutation in a patient with epileptic encephalopathy and employ electrophysiological analyses to establish channel properties that could underlie epileptogenesis: namely, inhibition by high [Cl−]i and loss of exclusive selectivity to K+. Furthermore, primary neurons expressing Ph240Leu display a hyperexcitable phenotype. Keywords: seizures, epileptic encephalopathy, ion channels, potassium channels, Slick, KCNT2, selectivity, Xenopus oocytes, Slack, KCNT1

BackgroundMutations in the gene encoding stimulator of interferon genes (STING) underlie a type I interferon (IFN) associated disease, STING-associated vasculopathy with onset in infancy (SAVI). Patients suffer cutaneous vasculopathy and interstitial lung disease, but are not known to suffer life-threatening infection.CaseWe describe a child who presented with Pneumocystis jirovecii pneumonia in early life, from which he recovered. He went on to suffer failure to thrive, developmental delay, livedo reticularis, and vesicular rash, but without cutaneous vasculitis, and with normal C-reactive protein and erythrocyte sedimentation rates. At 3 years of age, he developed life-threatening pulmonary hypertension.MethodsWhole genome sequencing (WGS) was performed using the Illumina HiSeqX10 platform and the Seave platform was used for bioinformatic analysis. mRNA expression of IFN-stimulated genes and inflammatory cytokines from peripheral blood mononuclear cells was determined by quantitative polymerase chain reaction. Luciferase assay was used to model IFNβ and NF-κB activity in vitro.ResultsWGS revealed a de novo mutation p.Arg284Ser in STING at an amino acid previously associated with SAVI. Although this mutation did not fall in the dimerization domain (DD), mRNA analysis revealed constitutive IFN-gene activation consistent with an interferonopathy, which correlated to STING activation in vitro. The patient was treated with corticosteroids and the JAK inhibitor Ruxolitinib, resulting in a rapid improvement of pulmonary hypertension, general well-being, and resolution of the IFN gene signature. However, he did go on to evolve a nasal septal erosion suggesting incomplete control of disease.ConclusionThis case provides molecular evidence to support the p.Arg284Ser variant in STING exerting pathogenicity through a gain-of-function mechanism. The lack of cutaneous vasculitis or elevated systemic inflammatory markers, and the occurrence of an opportunistic infection are notable, and raise the possibility that variants outside the STING DD may potentially manifest with an atypical SAVI phenotype. Nevertheless, there was an objective clinical improvement in response to JAK inhibition.