Abstract We first described the 2019 novel coronavirus infection in 10 children occurring in areas other than Wuhan. The coronavirus diseases in children are usually mild and epidemiological exposure is a key clue to recognize pediatric case. Prolonged virus shedding is observed in respiratory tract and feces at the convalescent stage.

ObjectiveType 2 diabetes mellitus is increasing in young adults, and greater adiposity is considered a major risk factor. However, whether there is an association between obesity and diabetes and how this might be impacted by age is not clear. Therefore, we investigated the association between body mass index (BMI) and diabetes across a wide range of age groups (20–30, 30–40, 40–50, 50–60, 60–70 and ≥70 years old).DesignWe performed a retrospective cohort study using healthy screening programme data.SettingA total of 211 833 adult Chinese persons >20 years old across 32 sites and 11 cities in China (Shanghai, Beijing, Nanjing, Suzhou, Shenzhen, Changzhou, Chengdu, Guangzhou, Hefei, Wuhan, Nantong) were selected for the study; these persons were free of diabetes at baseline.Primary and secondary outcome measuresFasting plasma glucose levels were measured and information regarding the history of diabetes was collected at each visit. Diabetes was diagnosed as fasting plasma glucose ≥7.00 mmol/L and/or self-reported diabetes. Patients were censored at the date of diagnosis or the final visit, whichever came first.ResultsWith a median follow-up of 3.1 years, 4174 of the 211 833 participants developed diabetes, with an age-adjusted incidence rate of 7.35 per 1000 persons. The risk of incident diabetes increased proportionally with increasing baseline BMI values, with a 23% increased risk of incident diabetes with each kg/m2 increase in BMI (95% CI 1.22 to 1.24). Across all age groups, there was a linear association between BMI and the risk of incident diabetes, although there was a stronger association between BMI and incident diabetes in the younger age groups (age×BMI interaction, p<0.0001).ConclusionsAn increased BMI is also independently associated with a higher risk of developing diabetes in young adults and the effects of BMI on incident diabetes were accentuated in younger adults.

Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear correlations between variant type and clinical features have not been observed so far. Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom. In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches.

The majority of children with Dravet syndrome (DS) are caused by de novo SCN1A mutations. To investigate the origin of the mutations, we developed and applied a new method that combined deep amplicon resequencing with a Bayesian model to detect and quantify allelic fractions with improved sensitivity. Of 174 SCN1A mutations in DS probands which were considered “de novo” by Sanger sequencing, we identified 15 cases (8.6%) of parental mosaicism. We identified another five cases of parental mosaicism that were also detectable by Sanger sequencing. Fraction of mutant alleles in the 20 cases of parental mosaicism ranged from 1.1% to 32.6%. Thirteen (65% of 20) mutations originated paternally and seven (35% of 20) maternally. Twelve (60% of 20) mosaic parents did not have any epileptic symptoms. Their mutant allelic fractions were significantly lower than those in mosaic parents with epileptic symptoms (P = 0.016). We identified mosaicism with varied allelic fractions in blood, saliva, urine, hair follicle, oral epithelium, and semen, demonstrating that postzygotic mutations could affect multiple somatic cells as well as germ cells. Our results suggest that more sensitive tools for detecting low‐level mosaicism in parents of families with seemingly “de novo” mutations will allow for better informed genetic counseling.

Objective Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and genotype–phenotype correlations of a large EIMFS cohort. Methods Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study. Results We ascertained 135 patients from 128 unrelated families. Ninety‐three of 135 (69%) had causative variants (42/55 previously reported) across 23 genes, including 9 novel EIMFS genes: de novo dominant GABRA1, GABRB1, ATP1A3; X‐linked CDKL5, PIGA; and recessive ITPA, AIMP1, KARS, WWOX. The most frequently implicated genes were KCNT1 (36/135, 27%) and SCN2A (10/135, 7%). Mosaicism occurred in 2 probands (SCN2A, GABRB3) and 3 unaffected mothers (KCNT1). Median age at seizure onset was 4 weeks, with earlier onset in the SCN2A, KCNQ2, and BRAT1 groups. Epileptic spasms occurred in 22% patients. A total of 127 patients had severe to profound developmental impairment. All but 7 patients had ongoing seizures. Additional features included microcephaly, movement disorders, spasticity, and scoliosis. Mortality occurred in 33% at median age 2 years 7 months. Interpretation We identified a genetic cause in 69% of patients with EIMFS. We highlight the genetic heterogeneity of EIMFS with 9 newly implicated genes, bringing the total number to 33. Mosaicism was observed in probands and parents, carrying critical implications for recurrence risk. EIMFS pathophysiology involves diverse molecular processes from gene and protein regulation to ion channel function and solute trafficking. ANN NEUROL 2019;86:821–831

Postzygotic single-nucleotide mutations (pSNMs) have been studied in cancer and a few other overgrowth human disorders at whole-genome scale and found to play critical roles. However, in clinically unremarkable individuals, pSNMs have never been identified at whole-genome scale largely due to technical difficulties and lack of matched control tissue samples, and thus the genome-wide characteristics of pSNMs remain unknown. We developed a new Bayesian-based mosaic genotyper and a series of effective error filters, using which we were able to identify 17 SNM sites from ∼80× whole-genome sequencing of peripheral blood DNAs from three clinically unremarkable adults. The pSNMs were thoroughly validated using pyrosequencing, Sanger sequencing of individual cloned fragments, and multiplex ligation-dependent probe amplification. The mutant allele fraction ranged from 5%-31%. We found that C→T and C→A were the predominant types of postzygotic mutations, similar to the somatic mutation profile in tumor tissues. Simulation data showed that the overall mutation rate was an order of magnitude lower than that in cancer. We detected varied allele fractions of the pSNMs among multiple samples obtained from the same individuals, including blood, saliva, hair follicle, buccal mucosa, urine, and semen samples, indicating that pSNMs could affect multiple sources of somatic cells as well as germ cells. Two of the adults have children who were diagnosed with Dravet syndrome. We identified two non-synonymous pSNMs in SCN1A, a causal gene for Dravet syndrome, from these two unrelated adults and found that the mutant alleles were transmitted to their children, highlighting the clinical importance of detecting pSNMs in genetic counseling.

A novel polypeptide hydrogel has been synthesized by crosslinking poly(L-glutamic acid) (PLG) with poly(ethylene glycol) (PEG). The PLG-PEG hydrogel was shown to be highly hydrophilic, and the extent of swelling varied with pH, increasing at higher ionization of the PLG. Aside from electrostatic effects, such as ion-ion repulsion and internal ion osmotic pressure, circular dichroism studies showed that swelling response to pH also is affected by secondary structural attributes associated with the polypeptide backbone. Modification of the polypeptide by changing its hydrophobicity and degree of ionization was an effective method for altering the overall extent of pH-responsive swelling. Rapid de-swelling (contraction) was observed when the PLG-PEG hydrogel was transferred from high to low pH buffer solution, and this swelling/de-swelling behavior was reversible over repeated cycles. Drug release from swollen hydrogels was examined using the model protein lysozyme. Rapid de-swelling of the hydrogel was found to be an effective means of facilitating lysozyme release. The crosslinking of synthetic polypeptides with PEG appears to be a highly versatile approach to the preparation of pH-responsive biodegradable hydrogels.

Summary Objective Mutations in SCN8A, a voltage‐gated sodium‐channel type VIII alpha subunit gene, have recently been recognized as one of the pathogenic mechanisms leading to epilepsy and intellectual/developmental disabilities (IDDs). The aim of this study was to detect SCN8A mutations in Chinese patients with epilepsy of unknown etiology and ID/DD. Methods We used targeted next‐generation sequencing to identify SCN8A mutations in Chinese patients with epilepsy of unknown etiology and IDDs. A filter process was performed to prioritize rare variants of potential functional significance. Sanger sequencing confirmed the variants and determined the parental origin. We followed all patients with SCN8A mutations in our cohort and analyzed their clinical data. Results Five de novo SCN8A mutations were identified, including four novel mutations (p.Ala890Thr, p.Leu407Phe, p.Arg850Gln, and p.Ser1596Cys) and one reported (p.Arg1617Gln). Polyphen2 and SIFT software predicted that all five mutations probably damaged Nav1.6 protein function; Mutation Taster indicated that all mutations were disease‐causing. Three of these five patients were controlled well by sodium channel blockers (SCBs). Two of these three patients remained seizure free for 6 and 1.5 months, respectively. One patient had sudden unexpected death in epilepsy (SUDEP) at the age of 1 year and 4 months. Significance Five SCN8A mutations were first reported in Chinese patients with epilepsy and ID/DD, expanding the phenotype and mutation spectrum of SCN8A mutations. Although three of these patients were controlled well by SCBs in our study, the effectiveness of SCBs should be validated in more patients with epilepsy caused by SCN8A mutations in the future. One of our five patients had sudden unexpected death in epilepsy SUDEP, suggesting that we should pay more attention to SUDEP in epileptic patients with SCN8A mutations.