SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups.

Aims To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. Methods and results A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE. Conclusion In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function

Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects’ cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis

The Effect of an After-School Physical Activity Program on Children’s Cognitive, Social, and Emotional Health during the COVID-19 Pandemic in Nova Scotia

Children’s physical activity participation declined during the COVID-19 pandemic, and these negative changes could lead to longer-term impacts on children’s cognitive, social, and emotional health. Purpose: To determine parent/caregivers’ perceptions of their children’s cognitive function, peer and family relationships, life satisfaction, physical activity, sleep, positive affect, and global health, before and after participating in the Build Our Kids’ Success (BOKS) programming at after-school programs in Fall 2020. Methods: Parents of children participating in the BOKS programming at after-school programs in Nova Scotia, Canada, were recruited. At baseline, 159 parents completed the National Institutes of Health (NIH) Patient-Reported Outcomes Measures Information System (PROMIS) parent-proxy questionnaire, and 75 parents completed the measures at follow-up. Independent t-tests were used to determine if there were differences between baseline and follow-up Parent Proxy Questionnaire data. Results: All NIH PROMIS outcome variables at baseline and follow-up were within normal limits (Adjusted T-Scores: 46.67 ± 7.15 to 50.04 ± 7.13). There were no significant differences in life satisfaction (t(188) = −1.05, p = 0.30), family relationships (t(189) = 0.31, p = 0.76), cognitive function (t(199) = −1.16, p = 0.25), peer relationships (t(192) = −1.86, p = 0.06), positive affect (t(195) = 0.25, p = 0.81), global health (t(216) = −0.43, p = 0.67), physical activity (t(202) = 0.787, p = 0.732), sleep disturbance (t(193) = 1.72, p = 0.087), or psychological stress (t(196) = 1.896, p = 0.059), from baseline to follow-up. Conclusions: Parent-proxy questionnaires suggested that the BOKS programming had a protective effect on children’s health behaviours and cognitive, social, and emotional health as values remained within normal limits and were not impacted by the public health restrictions during the second wave of the COVID-19 pandemic in Nova Scotia

The Impact of an After-School Physical Activity Program on Children’s Physical Activity and Well-Being during the COVID-19 Pandemic: A Mixed-Methods Evaluation Study

Introduction: This study evaluated the impact of the Build Our Kids’ Success (BOKS) after-school program on children’s physical activity (PA) and well-being during the COVID-19 pandemic. Methods: Program leaders, children, and their parents were recruited from after-school programs in Nova Scotia, Canada, that delivered BOKS programming in Fall 2020. After participating, Grade 4–6 children (n = 14) completed the Physical Literacy Assessment for Youth Self (PLAYself), Physical Activity Questionnaire for Older Children (PAQ-C), the Physical Activity Enjoyment Scale (PACES), and 5 National Institutes of Health (NIH) Patient-Reported Outcomes Measures Information System (PROMIS) scales. Children (n = 7), parents (n = 5), and program leaders (n = 3) completed interviews, which were analyzed for themes inductively. Results: The average PAQ-C score was 2.70 ± 0.48, PLAYself was 68.23 ± 13.12, and PACES was 4.22 ± 0.59 (mean ± SD). NIH PROMIS scores were below standard means (cognitive function, family relationships) or within normal limits (peer relationships, positive affect, and life satisfaction). A thematic analysis of interviews revealed that children’s PA levels were impacted by the pandemic and that BOKS positively impacted children’s physical well-being and integrated well with school-based activities. Conclusions: Participation in BOKS provided an overall positive experience and may have mitigated COVID-19-related declines in PA in well-being. The results of this evaluation can inform future physically-active after-school programming

Erratum: Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects' cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis