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Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11–13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients’ phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype. Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2, 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant. All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990–1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints. This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families.

Background. Youths with type 1 diabetes transitioning from pediatric to adult care are known to experience significant glycemic excursions and medical complications. Diabetes distress and transition readiness are two potentially related constructs involved in this transition process, but the relationship between them has not been extensively studied. Hypothesis. Lower diabetes distress is associated with increased transition readiness among youths with type 1 diabetes transitioning to adult care. Subjects. One hundred one adolescents and emerging adults with type 1 diabetes transitioning to adult care complete data in 63 study participants. Methods. In this cross-sectional study, we collected diabetes distress scale scores (via T1-DDS) and transition readiness scores (via Am I ON TRAC) at the last pediatric diabetes visit. We fitted regression models to estimate the relationship between T1-DDS scores and ON TRAC scores. Results. The total mean T1-DDS score was associated with ON TRAC knowledge score (β = −2.73, 95% CI −4.41,−1.06, p=0.002), behavior score (β = −2.61, 95% CI −4.39,−0.84, p=0.005), and transition readiness indicator (β = −0.18, −0.34,−0.01, p=0.03). Multiple T1-DDS subscales were associated with ON TRAC knowledge score: powerlessness, management distress, negative social perceptions, eating distress, physician distress, and family/friend distress. Multiple T1-DDS subscales were also associated with ON TRAC behavior score: management distress, negative social perceptions, eating distress, and family/friend distress. Conclusions. Diabetes distress and transition readiness have an inversely proportional relationship in youths with type 1 diabetes transitioning to adult care. Targeting diabetes distress may also improve transition readiness (and vice versa) in this population.

Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy with severe central hypoventilation. CCHS results from a mutation in the paired-like homeobox 2B gene ( ). In addition to hypoventilation, patients with CCHS display a wide array of autonomic nervous system abnormalities, including decreased heart rate variability and abrupt sinus pauses, esophageal dysmotility, abnormal pupillary light response, and temperature dysregulation, to name a few. To date, there has been no documentation of a child with both CCHS and hyperthyroidism. We report the case of a young child with CCHS who presented with tachycardia, which was later found to be due to Grave’s disease, after many months of investigation.

Introduction: Adolescents with type 1 diabetes (T1D) experience ongoing deterioration in their glycemic control as they transition to young adulthood.1 Several trials have evaluated possible transition interventions to ameliorate the care gap between pediatric and adult services in T1D care, although it remains unclear which are the most appropriate.2,3 In this pragmatic study, we sought to determine whether the change in quality of life pre- and post-transition was different between adolescents with T1D accessing a transition program versus those who did not. Methods: Between 2016-2018, we recruited 68 adolescents with T1D at their last pediatric diabetes clinic visit from a tertiary diabetes center without a structured transition program (control group) and 33 from a community-based outreach clinic with a transition program (intervention group) consisting of a transition coordinator, joint transition clinics, and pediatric and adult clinics located in the same building. At the time of transition and at one-year post-transition, we conducted chart reviews and administered surveys, including the SF-8 quality of life questionnaire. Analysis included descriptive statistics and linear regression models. Results: The control and intervention groups had the following characteristics, respectively: age at transition 18.4 years vs. 20.5 years (p<0.001); female 47% vs. 55% (p=0.49); average A1C at the time of transition 8.2% vs. 9.1% (p=0.0053). There was no statistically significant difference in the change in SF-8 scores for each of the eight domains (general health, physical functioning, role physical, bodily pain, vitality, social functioning, mental health, and role emotional) between the two groups. However, older age at transition was associated with an improvement in SF-8 vitality domain scores between the pre- and post-transition timepoints (p=0.034). Female sex was associated with a worsening in SF-8 vitality domain (p=0.004) and social functioning domain (p=0.015) scores between the pre- and post-transition timepoints. Finally, higher average A1C in the year prior to transition was associated with a worsening in SF-8 role physical domain scores between the pre- and post-transition timepoints (p=0.002). Conclusions: Quality of life scores in the vitality domain improved in the first year post-transition amongst young adults with T1D who transitioned at an older age, suggesting that a later transition may benefit adolescents with T1D. Additionally, worsening quality of life scores amongst young women and in those with higher pre-transition A1Cs suggest that these populations may require more specialized care at the time of transition. References: 1. Foster et al. Diabetes Technol Ther. 2019;21(2):66-72. 2. White et al. Lancet Child Adolesc Health. 2017;1(4):274-83. 3. Spaic et al. Diabetes Care. 2019;42(6):1018-26.

Investigation of the mechanisms responsible for aggressive neuroblastoma and its poor prognosis is critical to identify novel therapeutic targets and improve survival. Enhancer of Zeste Homolog 2 (EZH2) is known to play a key role in supporting the malignant phenotype in several cancer types and knockdown of EZH2 has been shown to decrease tumorigenesis in neuroblastoma cells. We hypothesized that the EZH2 inhibitor, GSK343, would affect cell proliferation and viability in human neuroblastoma. We utilized four long-term passage neuroblastoma cell lines and two patient-derived xenolines (PDX) to investigate the effects of the EZH2 inhibitor, GSK343, on viability, motility, stemness and in vivo tumor growth. Immunoblotting confirmed target knockdown. Treatment with GSK343 led to significantly decreased neuroblastoma cell viability, migration and invasion, and stemness. GSK343 treatment of mice bearing SK-N-BE(2) neuroblastoma tumors resulted in a significant decrease in tumor growth compared to vehicle-treated animals. GSK343 decreased viability, and motility in long-term passage neuroblastoma cell lines and decreased stemness in neuroblastoma PDX cells. These data demonstrate that further investigation into the mechanisms responsible for the anti-tumor effects seen with EZH2 inhibitors in neuroblastoma cells is warranted.

Plant transformation has enabled fundamental insights into plant biology and revolutionized commercial agriculture. Unfortunately, for most crops, transformation and regeneration remain arduous even after more than 30 years of technological advances. Genome editing provides novel opportunities to enhance crop productivity but relies on genetic transformation and plant regeneration, which are bottlenecks in the process. Here, we review the state of plant transformation and point to innovations needed to enable genome editing in crops. Plant tissue culture methods need optimization and simplification for efficiency and minimization of time in culture. Currently, specialized facilities exist for crop transformation. Single-cell and robotic techniques should be developed for high-throughput genomic screens. Plant genes involved in developmental reprogramming, wound response, and/or homologous recombination should be used to boost the recovery of transformed plants. Engineering universal Agrobacterium tumefaciens strains and recruiting other microbes, such as Ensifer or Rhizobium, could facilitate delivery of DNA and proteins into plant cells. Synthetic biology should be employed for de novo design of transformation systems. Genome editing is a potential game-changer in crop genetics when plant transformation systems are optimized.

Patients with glucocorticoid (GC) excess, Cushing's syndrome, develop a classic phenotype characterized by central obesity and insulin resistance. GCs are known to increase the release of fatty acids from adipose, by stimulating lipolysis, however, the impact of GCs on the processes that regulate lipid accumulation has not been explored. Intracellular levels of active GC are dependent upon the activity of 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) and we have hypothesized that 11β-HSD1 activity can regulate lipid homeostasis in human adipose tissue (Chub-S7 cell line and primary cultures of human subcutaneous (sc) and omental (om) adipocytes. Across adipocyte differentiation, lipogenesis increased whilst β-oxidation decreased. GC treatment decreased lipogenesis but did not alter rates of β-oxidation in Chub-S7 cells, whilst insulin increased lipogenesis in all adipocyte cell models. Low dose Dexamethasone pre-treatment (5 nM) of Chub-S7 cells augmented the ability of insulin to stimulate lipogenesis and there was no evidence of adipose tissue insulin resistance in primary sc cells. Both cortisol and cortisone decreased lipogenesis; selective 11β-HSD1 inhibition completely abolished cortisone-mediated repression of lipogenesis. GCs have potent actions upon lipid homeostasis and these effects are dependent upon interactions with insulin. These in vitro data suggest that manipulation of GC availability through selective 11β-HSD1 inhibition modifies lipid homeostasis in human adipocytes.

The adverse metabolic effects of prescribed and endogenous glucocorticoid (GC) excess, Cushing syndrome, create a significant health burden. We found that tissue regeneration of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), rather than circulating delivery, is critical to developing the phenotype of GC excess; 11β-HSD1 KO mice with circulating GC excess are protected from the glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, and dermal atrophy of Cushing syndrome. Whereas liver-specific 11β-HSD1 KO mice developed a full Cushingoid phenotype, adipose-specific 11β-HSD1 KO mice were protected from hepatic steatosis and circulating fatty acid excess. These data challenge our current view of GC action, demonstrating 11β-HSD1, particularly in adipose tissue, is key to the development of the adverse metabolic profile associated with circulating GC excess, offering 11β-HSD1 inhibition as a previously unidentified approach to treat Cushing syndrome.

Background US research organizations increasingly are supporting patient and stakeholder engagement in health research with a goal of producing more useful, relevant and patient‐centered evidence better aligned with real‐world clinical needs. The Patient‐Centered Outcomes Research Institute (PCORI) engages patients, family caregivers and other health‐care stakeholders, including clinicians, payers and policymakers, as active partners in prioritizing, designing, conducting and disseminating research as a key strategy to produce useful evidence for health‐care decision making. Objective To inform effective engagement practices and policies, we sought to understand what motivates patients and caregivers to engage as partners on PCORI‐funded research projects and how such engagement changed their lives. Methods We conducted thematic analysis of open‐ended survey responses from 255 patients, family caregivers and individuals from advocacy and community‐based organizations who engaged as partners on 139 PCORI‐funded research projects focusing on a range of health conditions. Results Partners' motivations for engaging in research were oriented primarily towards benefiting others, including a desire to improve patients' lives and to support effective health‐care interventions. In addition to feeling they made a positive difference, many partners reported direct benefits from engagement, such as new relationships and improved health habits. Discussion and Conclusions By identifying patient and caregiver motivations for engaging in research partnerships and what they get out of the experience, our study may help research teams and organizations attract partners and foster more satisfying and sustainable partnerships. Our findings also add to evidence that engagement benefits the people involved as partners, strengthening the case for more widespread engagement.

Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance. Epidemiological studies have associated circulating levels of the amino acid glycine with cardiometabolic outcomes. Here, in a genome-wide meta-analysis of 80,003 individuals, Wittemans et al. identify 22 novel genetic loci for glycine and find a causal relationship with coronary heart disease using MR.