Beyond samples: A metric revealing more connections of gut microbiota between individuals.

Studies of gut microbiota explore their complicated connections between individuals of different characteristics by applying different metrics to abundance data obtained from fecal samples. Although classic metrics are capable to quantify differences between samples, the microbiome of fecal sample is not a good surrogate for the gut microbiome of individuals because the microbial populations of the distal colon does not adequately represent that of the entire gastrointestinal tract. To overcome the deficiency of classic metrics in which the differences can be measured between the samples analyzed, but not the corresponding populations, we propose a metric for representing composition differences in the gut microbiota of individuals. Our investigation shows this metric outperforms traditional measures for multiple scenarios. For gut microbiota in diverse geographic populations, this metric presents more explainable data variance than others, not only in regular variance analysis but also in principle component analysis and partition analysis of biologic characteristics. With time-series data, the metric further presents a strong correlation with the time interval of serial sampling. Our findings suggest that the metric is robust and powerfully detects the intrinsic variations in gut microbiota. The metric holds promise for revealing more relations between gut microbiota and human health.

Age-Dependent Risks of Incidence and Mortality of COVID-19 in Hubei Province and Other Parts of China.

The new coronavirus SARS-CoV-2 pandemic of early 2020 poses an enormous challenge to global public health. Coronavirus Disease 2019 (COVID-19) caused by the virus has spread rapidly throughout the world, taking thousands of lives in just over 2 months. It is critical to refine the incidence and mortality risks of COVID-19 for the effective management of the general public and patients during the outbreak. In this report, we investigate the incidence and mortality risks of the infection by analyzing the age composition of 5,319 infected patients, 76 fatal cases, and 1,144,648 individuals of the general public in China. Our results show a relatively low incidence risk for young people but a very high mortality risk for seniors. Notably, mortality risk could be as high as 0.48 for people older than 80 years. Furthermore, our study suggests that a good medical service can effectively reduce the mortality rate of the viral infection to 1% or less.

Vertically Aligned and Ordered Arrays of 2D MCo2S4@Metal with Ultrafast Ion/Electron Transport for Thickness-Independent Pseudocapacitive Energy Storage.

Pseudocapacitance holds great promise for energy density improvement of supercapacitors, but electrode materials show practical capacity far below theoretical values due to limited ion diffusion accessibility and/or low electron transferability. Herein, inducing two kinds of straight ion-movement channels and fast charge storage/delivery for enhanced reaction kinetics is proposed. Very thick electrodes consisting of vertically aligned and ordered arrays of NiCo2S4-nanoflake-covered slender nickel columns (NCs) are achieved via a scalable route. The vertical standing ∼5 nm ultrathin NiCo2S4 flakes build a porous covering with straight ion channels without the "dead volume", leading to thickness-independent capacity. Benefiting from the architecture acting as a "superhighway" for ultrafast ion/electron transport and providing a large surface area, high electrical conductivity, and abundant availability of electrochemical active sites, the NiCo2S4@NC-array electrode achieves a specific capacity up to 486.9 mAh g-1. The electrode even can work with a high specific capacity of 150 mAh g-1 at a very high current density of 100 A g-1. In particular, due to the advanced structure features, the electrode exhibits excellent flexibility with a unexpected improvement of capacity when being largely bent and excellent cycling stability with an obvious resistance decrease after the cycles. An asymmetric pseudocapacitor applying the NiCo2S4@NC-array as a positive electrode achieves an energy density of 66.5 Wh kg-1 at a power density of 400 W kg-1, superior to the most reported values for asymmetric devices with NiCo2S4 electrodes. This work provides a scalable approach with mold-replication-like simplicity toward achieving thickness-independent electrodes with ultrafast ion/electron transport for energy storage.

The first familial NSD2 cases with a novel variant in a Chinese father and daughter with atypical WHS facial features and a 7.5-year follow-up of growth hormone therapy.

BACKGROUND: Wolf-Hirschhorn syndrome is a well-characterized genomic disorder caused by 4p16.3 deletions. Wolf-Hirschhorn syndrome patients exhibit characteristic facial dysmorphism, growth retardation, developmental delay, intellectual disability and seizure disorders. Recently, NSD2 gene located within the 165 kb Wolf-Hirschhorn syndrome critical region was identified as the key causal gene responsible for most if not all phenotypes of Wolf-Hirschhorn syndrome. So far, eight NSD2 loss of function variants have been reported in patients from different parts of the world, all were de novo variants. METHODS: In our study, we performed whole exome sequencing for two patients from one family. We also reviewed more NSD2 mutation cases in pervious literature. RESULTS: A novel loss of function NSD2 variant, c.1577dupG (p.Asn527Lysfs*14), was identified in a Chinese family in the proband and her father both affected with intellectual disability. After reviewing more NSD2 mutation cases in pervious literature, we found none of them had facial features that can be recognized as Wolf-Hirschhorn syndrome. In addition, we have given our proband growth hormone and followed up with this family for 7.5 years. CONCLUSIONS: Here we reported the first familial NSD2 variant and the long-term effect of growth hormone therapy for patients. Our results suggested NSD2 mutation might cause a distinct intellectual disability and short stature syndrome.

The first two Chinese Myhre syndrome patients with the recurrent SMAD4 pathogenic variants: Functional consequences and clinical diversity.

Myhre syndrome is a rare autosomal dominant multi-organ disorder characterized by growth retardation, skeletal anomalies, muscular hypertrophy, joint stiffness, facial dysmorphism, deafness, cardiovascular disease, and abnormal sexual development. Here we described the first two Chinese Myhre syndrome patients diagnosed by whole-exome sequencing. They both had de novo c.1498A > G (p.Ile500Val) variant in SMAD4 and presented with key characteristics of Myhre syndrome but also revealed uncommon features (polydactyly in the girl and precocious puberty in the boy). We performed functional analysis on four previously reported SMAD4 pathogenic variants in Myhre syndrome patients using dual-luciferase assay. Our results revealed that the pathogenic variants resulted in a variable degree of increased transcription activity of target genes that contain the minimal SMAD binding elements in their promoter regions. The boy responded to the recombinant human growth hormone treatment with improved height but also led to hyperinsulinemia and advanced bone age. Because of his precocious puberty, we subsequently combined the recombinant human growth hormone and gonadotrophin-releasing hormone agonist treatments, which resulted in overall improved height. We reviewed the sexual features of reported Myhre syndrome cases and discussed the possible mechanism of SMAD4 variants in Myhre syndrome that lead to the abnormal hypothalamic-pituitary-gonadal axis.

Novel pathogenic RECQL4 variants in Chinese patients with Rothmund-Thomson syndrome.

BACKGROUND: Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder mainly characterized by cutaneous poikiloderma, sparse hair, short stature and skeletal defects. Deleterious mutations in the RecQ-like DNA helicase type 4 (RECQL4) gene have been detected in approximately two-thirds of RTS cases. METHODS: Three Chinese patients from two unrelated families were enrolled for clinical evaluation. Targeted next-generation sequencing (NGS) using a custom panel consisting of 705 short-stature-related genes was performed for the probands. Variants detected by NGS were confirmed by Sanger sequencing and examined in family members. RESULTS: The probands presented with characteristic features of severe growth delay, poikiloderma mostly on the face, buttocks and extremities, sparse or absent hair, eyelashes, and eyebrows, forearm reduction defects, small hands with hypoplasia of the middle phalanx (little finger) in one of the probands, epicanthus, hypertelorism, and dental abnormalities. In addition, novel auricle features and other rare facial features, including narrow palpebral fissure, depressed nasal bridge, and small chin were exhibited. Four novel RECQL4 variants were identified, including three pathogenic frameshift variants, c.1724_1725delAC, p.His575fs*7; c.2421dupT, p.Asp808*; c.1770_1807del, p.Pro591fs*2, and one likely pathogenic missense variant, c.691G>A, p.Gly231Ser. CONCLUSION: Our study expands the mutational spectrum of RECQL4 gene and reveals novel phenotypes observed in Chinese RTS patients.

Mosaic UPD(7q)mat in a patient with silver Russell syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) is one of the imprinting disorders characterized by prenatal and postnatal growth restriction, relative macrocephaly, body asymmetry and characteristic facial features. ~ 10% of SRS cases are known to be associated with maternal uniparental disomy of chromosome 7 (UPD(7)mat). Mosaic maternal segmental UPD of 7q (UPD(7q)mat) is very rare, had only been described in one case before. CASE PRESENTATION: We reported a second case of mosaic segmental UPD involving 7q. The patient presented with dysmorphic features including thin and short stature, triangular face, moderate protruding forehead, relative macrocephaly, fifth toe clinodactyly and irregular teeth, meeting the clinical diagnosed criteria of SRS. This case indicated that ~ 80% of mosaic UPD(7q)mat lead to the manifestation of main phenotypes of Silver-Russell syndrome. CONCLUSIONS: Our case support the notion that there are genes control postnatal growth on long arm of chromosome 7 and indicate that ~ 80% of UPD(7q)mat mosaicism level was contributed to the SRS phenotype.

Prenatal and early diagnosis of Chinese 3-M syndrome patients with novel pathogenic variants.

BACKGROUND: 3-M syndrome is a clinically recognizable yet under-diagnosed primordial growth retardation disorder. Molecular testing for CUL7, OBSL1 or CCDC8 genes can provide confirmed diagnosis for patients at prenatal or early age. So far, the clinical and molecular features of Chinese 3-M syndrome patients have not been reported. METHODS: In this article, the authors performed prenatal and early diagnosis of Chinese patients with 3-M syndrome by Next-Generation Sequencing. RESULTS: The authors reported six unrelated Chinese 3-M syndrome patients. Five of the six patients were diagnosed before two years of age including one prenatal case. The authors identified six novel pathogenic variants and five previously reported pathogenic variants. The authors' clinical evaluations indicated that Chinese 3-M syndrome patients share similar recognizable features as those reported in patients of other ethnic background. The authors noticed some uncommon features in this small cohort of Chinese patients such as delayed motor development at early ages, undelayed bone age and presence of lower eyelid fat pads. CONCLUSION: The authors' study of Chinese 3-M syndrome patients revealed novel mutations and clinical phenotypes.

Novel pathogenic ACAN variants in non-syndromic short stature patients.

BACKGROUND: Pathogenic variants of ACAN have been reported to cause spondyloepiphyseal dysplasia Kimberley type, spondyloepimetaphyseal dysplasia, familial osteochondritis dissecans and idiopathic short stature with normal to advanced bone age. A recent international cohort study significantly expanded the ACAN mutation spectrum, further delineated the heterogeneous clinical characteristics of ACAN mutation patients. The prevalence of ACAN mutation in short stature patients is yet unknown. METHODS: Here we set to assess the frequency of ACAN variants among a cohort of 218 Chinese children with non-syndromic short stature. RESULTS: We identified three novel truncating variants at the 5' end of ACAN gene. All these pathogenic variants co-segregate with severe short stature phenotype in families. In addition, none of the probands showed significant advanced bone age. All affected individuals showed no signs of significant dysmorphic features or skeletal abnormities. The prevalence of ACAN defect in this cohort is estimated to be 1.4% (3/218). It is higher among families with parents also affected with severe short stature, up to 7.0% (3/43) if parental height is <2.5 SD or 16.7% (3/18) if parental height is <3.0 SD. CONCLUSION: Our data suggest that ACAN mutation is a relative common cause of familial severe short stature.

Thyroglobulin gene mutations in Chinese patients with congenital hypothyroidism.

Mutations in Thyroglobulin (TG) are common genetic causes of congenital hypothyroidism (CH). But the TG mutation spectrum and its frequency in Chinese CH patients have not been investigated. Here we conducted a genetic screening of TG gene in a cohort of 382 Chinese CH patients. We identified 22 rare non-polymorphic variants including six truncating variants and 16 missense variants of unknown significance (VUS). Seven patients carried homozygous pathogenic variants, and three patients carried homozygous or compound heterozygous VUS. 48 out of 382 patients carried one of 18 heterozygous VUS which is significantly more often than their occurrences in control cohort (P < 0.0001). Unique to Asian population, the c.274+2T>G variant is the most common pathogenic variant with an allele frequency of 0.021. The prevalence of CH due to TG gene defect in Chinese population was estimated to be approximately 1/101,000. Our study uncovered ethnicity specific TG mutation spectrum and frequency.