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Abstract Hydrogels, provided that they integrate strength and toughness at desired high content of water, promise in load-bearing tissues such as articular cartilage, ligaments, tendons. Many developed strategies impart hydrogels with some mechanical properties akin to natural tissues, but compromise water content. Herein, a strategy deprotonation-complexation-reprotonation is proposed to prepare polyvinyl alcohol hydrogels with water content as high as ~80% and favorable mechanical properties, including tensile strength of 7.4 MPa, elongation of around 1350%, and fracture toughness of 12.4 kJ m−2. The key to water holding yet improved mechanical properties lies in controllable nucleation for refinement of crystalline morphology. With nearly constant water content, mechanical properties of as-prepared hydrogels are successfully tailored by tuning crystal nuclei density via deprotonation degree and their distribution uniformity via complexation temperature. This work provides a nucleation concept to design robust hydrogels with desired water content, holding implications for practical application in tissue engineering.

Our previous study found that Dunaliella parva WRINKLED1-like (DpWRI1-like) was a key regulatory factor of lipid biosynthesis in D. parva. DpWRI1-like gene and target genes of DpWRI1-like have been obtained in our previous study, but the interacting proteins of DpWRI1-like are unclear now, which has limited a deep understanding of the function of DpWRI1-like. Yeast two-hybrid was widely used to identify protein-protein interaction. In this study, the interacting proteins of DpWRI1-like were obtained using yeast two-hybrid technique to further realize the role of DpWRI1-like. Three important interacting proteins have the following predicted activities: acyl-CoA-binding domain-containing protein 6 (interacting protein 1, ACBD6), duplicated carbonic anhydrase (interacting protein 2, DCA) and DNA-binding transcription factor (interacting protein 3, TF). Bimolecular fluorescence complementation assay further validated the interaction between DpWRI1-like and interacting proteins ACBD6 and DCA. The further bioinformatics analyses of interacting proteins were conducted. Protein-protein docking indicated the strong affinity between DpWRI1-like and three interacting proteins. Since interacting proteins have been found to be related to lipid biosynthesis in other organisms, this study contributes to a deeper understanding of the role of DpWRI1-like in lipid synthesis. In conclusion, this study firstly reported three interacting proteins (ACBD6, DCA and TF) of DpWRI1-like related to lipid biosynthesis, and conducted their bioinformatics analyses, which would be conducive to a deep understanding of the function of DpWRI1-like in lipid biosynthesis.

BackgroundWith the aging of China's population, cognitive impairment in the elderly is receiving increasing public attention. Screening and intervention of people with mild cognitive impairment (MCI) are of great significance to prevent and reduce the occurrence of cognitive impairment.ObjectiveTo understand the prevalence and explore potential influencing factors of MCI in the elderly in Songjiang District, Shanghai, and to provide scientific basis for promoting early screening of cognitive impairment and precise intervention of MCI in the elderly in this area. MethodsA cross-sectional study design was adopted. From August to October 2022, using multi-stage random sampling, 1800 elderly residents aged 60 years and above were screened for cognitive impairment in 6 neighborhood/village committees in 6 towns in Songjiang District. The survey questionnaires included a sociodemographic questionnaire, a health status and lifestyle questionnaire, the Instrumental Activities of Daily Living (IADL), the Patient Health Questionnaire (PHQ-9), and the Mini-Mental State Examination (MMSE). Prevalence rates of MCI among the elderly by selected social demographic characteristics, health status, and lifestyle were estimated, and potential influencing factors of MCI were evaluated by binary logistic regression. ResultsA total of 209 elderly residents with MCI and 1591 healthy elderly residents were detected, and the prevalence of MCI in the elderly aged 60 and above was 11.6% in Songjiang District. Being physically active (OR=0.556, 95%CI: 0.399, 0.774) reduced the risk of MCI. Illiteracy (OR=1.810, 95%CI: 1.239, 2.644), primary school education level (OR=3.454, 95%CI: 2.342, 5.092), non-participation in social activities (OR=1.945, 95%CI: 1.360, 2.781), IADL damaged (OR=3.173, 95%CI: 2.137, 4.712), and depression (OR=1.957, 95%CI: 1.112, 3.443) increased the risk of MCI (P＜0.05). ConclusionThe prevalence of MCI among the elderly in Songjiang District is lower than the national average. Educational level, physical activity, participation in social activities, IADL, and depression may be the influencing factors of MCI in the elderly. It is recommended to carry out early screening, early detection, and early intervention for cognitive impairment in the elderly. Improving involvement in physical exercise and increasing participation in social activities are encouraged. Special attention should be paid to the needs of vulnerable groups such as low education level and disabled elderly during a community MCI intervention program.

Abstract Background Ovarian cancer (OC) has the worst prognosis among gynecological malignancies, most of which are found to be in advanced stage. Cell reduction surgery based on platinum-based chemotherapy is the current standard of treatment for OC, but patients are prone to relapse and develop drug resistance. The objective of this study was to identify a specific molecular target responsible for platinum chemotherapy resistance in OC. Results We screened the protein-coding gene Caldesmon (CALD1), expressed in cisplatin-resistant OC cells in vitro. The prognostic value of CALD1 was evaluated using survival curve analysis in OC patients treated with platinum therapy. The diagnostic value of CALD1 was verified by drawing a Receiver Operating Characteristic (ROC) curve using clinical samples from OC patients. This study analyzed data from various databases including Gene Expression Omnibus (GEO), Human Protein Atlas (HPA), The Cancer Cell Line Encyclopedia (CCLE), The Cancer Genome Atlas (TCGA), GEPIA 2, UALCAN, Kaplan–Meier (KM) plotter, LinkedOmics database, and String. Different expression genes (DEGs) between cisplatin-sensitive and cisplatin-resistant cells were acquired respectively from 5 different datasets of GEO. CALD1 was selected as a common gene from 5 groups DEGs. Online data analysis of HPA and CCLE showed that CALD1 was highly expressed in both normal ovarian tissue and OC. In TCGA database, high expression of CALD1 was associated with disease stage and venous invasion in OC. Patients with high CALD1 expression levels had a worse prognosis under platinum drug intervention, according to Kaplan–Meier (KM) plotter analysis. Analysis of clinical sample data from GEO showed that CALD1 had superior diagnostic value in distinguishing patients with platinum "resistant" and platinum "sensitive" (AUC = 0.816), as well as patients with worse progression-free survival (AUC = 0.741), and those with primary and omental metastases (AUC = 0.811) in ovarian tumor. At last, CYR61 was identified as a potential predictive molecule that may play an important role alongside CALD1 in the development of platinum resistance in OC. Conclusions CALD1, as a member of cytoskeletal protein, was associated with poor prognosis of platinum resistance in OC, and could be used as a target protein for mechanism study of platinum resistance in OC.

Abstract Background The relationship of testosterone and estradiol concentrations with cognitive function among community-dwelling older men was inconclusive. To examine the association of serum testosterone and estradiol concentrations with cognitive function in older men with or without vascular risk factors (VRFs). Methods This cross-sectional study consisted of 224 community-dwelling men aged 65–90 years in the Songjiang District of Shanghai, China. Serum testosterone and estradiol were measured by electrochemiluminescence immunoassay. The following five factors were defined as VRFs in this study: obesity, history of hypertension, diabetes, stroke, and coronary heart disease. Multivariable linear regression was used to examine the association of testosterone and estradiol with the Mini-Mental State Examination (MMSE) in participants with or without VRF. Restricted cubic spline (RCS) regression was performed to account for the nonlinearity of these associations. Results An inverted “U” shaped non-linear relationship was found between testosterone concentration and MMSE score in men with one VRF (P overall =.003, non-linear P =.002). Estradiol showed an inverted “U” shaped non-linear relationship with MMSE score independent of VRFs (men without VRF, P overall =.049, non-linear P =.015; men with one VRF, overall P =.007, non-linear P =.003; men with two or more VRFs, overall P =.009, non-linear P =.005). Conclusion In older men, an optimal level of sex steroid concentration may be beneficial to cognitive function and the VRFs should be considered when interpreting the relationship between sex steroid and cognitive function.

Background: Autosomal recessive intellectual developmental disorder-3 is caused by homozygous or compound heterozygous mutations in the CC2D1A gene. The disorder is characterized by intellectual disability (ID) and autism spectrum disorder (ASD). To date, 39 patients from 17 families with CC2D1A -related disorders have been reported worldwide, in whom only six pathogenic or likely pathogenic loss-of-function variants and three variants of uncertain significance (VUS) in the CC2D1A gene have been identified in these patients. Methods: We described a patient with ID from a non-consanguineous Chinese family and whole-exome sequencing (WES) was used to identify the causative gene. Results: The patient presented with severe ID and ASD, speech impairment, motor delay, hypotonia, slight facial anomalies, and finger deformities. Threatened abortion and abnormal fetal movements occurred during pregnancy with the proband but not his older healthy sister. WES analysis identified a homozygous nonsense variant, c.736C > T (p.Gln246Ter), in the CC2D1A gene. In addition, six novel likely pathogenic CC2D1A variants were identified by a retrospective review of the in-house database. Conclusions: This study expands the genetic and clinical spectra of CC2D1A-associated disorders, and may aid in increasing awareness of this rare condition. Our findings have provided new insights into the clinical heterogeneity of the disease and further phenotype-genotype correlation, which could help to offer scope for more accurate genetic testing and counseling to affected families.

Kabuki syndrome (KS) is a multiple congenital anomaly syndrome that is characterized by postnatal growth deficiency, hypotonia, short stature, mild-to-moderate intellectual disability, skeletal abnormalities, persistence of fetal fingertip pads, and distinct facial appearance. It is mainly caused by pathogenic/likely pathogenic variants in the KMT2D or KDM6A genes. Here, we described the clinical features of nine sporadic KS patients with considerable phenotypic heterogeneity. In addition to intellectual disability and short stature, our patients presented with a high prevalence of motor retardation and recurrent otitis media. We recommended that KS should be strongly considered in patients with motor delay, short stature, intellectual disability, language disorder and facial deformities. Nine KMT2D variants, four of which were novel, were identified by whole-exome sequencing. The variants included five nonsense variants, two frameshift variants, one missense variant, and one non-canonical splice site variant. In addition, we reviewed the mutation types of the pathogenic KMT2D variants in the ClinVar database. We also indicated that effective mRNA analysis, using biological materials from patients, is helpful in classifying the pathogenicity of atypical splice site variants. Pedigree segregation analysis may also provide valuable information for pathogenicity classification of novel missense variants. These findings extended the mutation spectrum of KMT2D and provided new insights into the understanding of genotype-phenotype correlations, which are helpful for accurate genetic counseling and treatment optimization.

Abstract Background Homozygous or compound heterozygous ROBO3 gene mutations cause horizontal gaze palsy with progressive scoliosis (HGPPS). This is an autosomal recessive disorder that is characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis. To date, almost 100 patients with HGPPS have been reported and 55 ROBO3 mutations have been identified. Methods We described an HGPPS patient and performed whole‐exome sequencing (WES) to identify the causative gene. Results We identified a missense variant and a splice‐site variant in the ROBO3 gene in the proband. Sanger sequencing of cDNA revealed the presence of an aberrant transcript with retention of 700 bp from intron 17, which was caused by a variation in the noncanonical splicing site. We identified five additional ROBO3 variants, which were likely pathogenic, and estimated the overall allele frequency in the southern Chinese population to be 9.44 × 10−4, by a review of our in‐house database. Conclusion This study has broadened the mutation spectrum of the ROBO3 gene and has expanded our knowledge of variants in noncanonical splicing sites. The results could help to provide more accurate genetic counseling to affected families and prospective couples. We suggest that the ROBO3 gene should be included in the local screening strategy.

Highlights A self-grinding exfoliation strategy that depends on mutual shear friction between flake graphite particles is successfully developed to prepare pristine graphene with largely enhanced yield and productivity. Bioinspired assembly of pristine graphene nanosheets to an interconnected aramid nanofiber network is achieved by a continuous sol-gel-film transformation strategy and generates a flexible yet highly thermoconductive film. Abstract Flexible yet highly thermoconductive materials are essential for the development of next-generation flexible electronic devices. Herein, we report a bioinspired nanostructured film with the integration of large ductility and high thermal conductivity based on self-exfoliated pristine graphene and three-dimensional aramid nanofiber network. A self-grinding strategy to directly exfoliate flake graphite into few-layer and few-defect pristine graphene is successfully developed through mutual shear friction between graphite particles, generating largely enhanced yield and productivity in comparison to normal liquid-based exfoliation strategies, such as ultrasonication, high-shear mixing and ball milling. Inspired by nacre, a new bioinspired layered structural design model containing three-dimensional nanofiber network is proposed and implemented with an interconnected aramid nanofiber network and high-loading graphene nanosheets by a developed continuous assembly strategy of sol–gel-film transformation. It is revealed that the bioinspired film not only exhibits nacre-like ductile deformation behavior by releasing the hidden length of curved aramid nanofibers, but also possesses good thermal transport ability by directionally conducting heat along pristine graphene nanosheets. Graphical abstract

Abstract Background Metabolic Syndrome (MetS) is a common health problem among older adults. Previous studies have revealed the relationship between sleep duration as well as global sleep status and MetS. Objectives This study aims to examine the association between the specific sleep characteristic and MetS as well as MetS components among community-dwelling old adults. Methods This cross-sectional study included 1499 community residents aged ≥ 60 years. Sleep characteristics were assessed using the Pittsburgh Sleep Quality Index (PSQI) and bed/rise time of the residents. Logistic regression analysis and multiple linear regression analysis were used to examine the associations between sleep characteristics and MetS as well as MetS components. A generalized additive model was built to assess the smooth relationship between triglyceride (TG) levels and sleep duration. Results Of the 1499 participants, 449 (30.0%) had MetS, and 443 (29.6%) had poor sleep quality. The rise time was found to be associated with MetS (> 6:00 vs. 5:00 ~ 6:00: adjusted OR (95%) = 1.77 (1.17–2.69), P = 0.007). For the MetS components, a U-shaped relationship was first revealed for sleep duration and TG levels (EDF = 1.85, P

Abstract Background Cognitive leisure activity, such as reading, playing mahjong or cards and computer use, is common among older adults in China. Previous studies suggest a negative correlation between cognitive leisure activity and cognitive impairment. However, the relationship between cognitive leisure activity and all-cause mortality has rarely been reported. Objectives This study aims to explore the relationships between cognitive leisure activity and all-cause mortality in a community-based older people cohort in China. Methods The current study sample comprised 4003 community residents aged ≥60 y who were enrolled in June 2015, and were followed up every year from 2015 to 2018. Reading, playing mahjong or cards and computer use were measured by questionnaires and summed into a cognitive leisure activity index (CLAI) score. Time-Dependent Cox Regression Model and Kaplan-Meier survival analysis were used to examine the association of cognitive leisure activity with all-cause mortality. Results During the 4-year follow-up of 4003 participants, 208 (5.2%) deaths were registered. Of all participants, 66.8, 26.7, 6.1 and 0.35% reported CLAI scores of 0, 1, 2 and 3, respectively. A strong association was noted between the CLA score and all-cause mortality (adjusted hazard ratio [HR] = 0.72, 95% confidence intervals [CI]: 0.54–0.97, P = 0.028). Stratified analysis suggested that a higher CLAI score was significantly associated with a decreased risk of all-cause mortality mainly among those who were male, aged ≥80 y, cognitively impaired, and not diagnosed with cancer (P

Abstract Background Neuronal ceroid lipofuscinosis type 5 (CLN5) is a rare form of neuronal ceroid lipofuscinoses (NCLs) which are a group of inherited neurodegenerative diseases characterized by progressive intellectual and motor deterioration, visual failure, seizures, behavioral changes and premature death. CLN5 was initially named Finnish variant late infantile NCL, it is now known to be present in other ethnic populations and with variable age of onset. Few CLN5 patients had been reported in Chinese population. Case presentation In this paper, we report the symptoms of a Chinese patient who suffer from developmental regression and grand mal epilepsy for several years. The DNA was extracted from peripheral blood of proband and both parents, and then whole exome sequencing was performed using genomic DNA. Both sequence variants and copy number variants (CNVs) were analyzed and classified according to guidelines. As the result, a novel frameshift mutation c.718_719delAT/p.Met240fs in CLN5 and a de novo large deletion at 13q21.33-q31.1 which unmasked the frameshift mutation were identified in the proband. Despite the large de novo deletion, which can be classified as a pathogenic copy number variant (CNV), the patient’s clinical presentation is mostly consistent with that of CLN5, except for early developmental delay which is believed due to the large deletion. Both variants were detected simultaneously by exome sequencing. Conclusions This is the first report of whole gene deletion in combination with a novel pathogenic sequence variant in a CLN5 patient. The two mutations detected with whole exome sequencing simultaneously proved the advantage of the sequencing technology for genetic diagnostics.

Abstract Background It is important to clarify the transitions and related factors of frailty for prevention of frailty. We evaluated the transitions of frailty among community-dwelling older adults and examined the predictors of the transitions. Methods A cohort study was conducted among 3988 community residents aged ≥60 years during 2015 and 2017. A multiple deficits approach was used to construct the Frailty Index (FI) according to the methodology of FI construction, and sociodemographic characteristics and lifestyles were also collected in 2015. After 2-year follow-up, the transitions of frailty between baseline and were evaluated. Multinomial logistic regressions were used to examine associations between predictors and the transitions of frailty. Results The proportion of robust, prefrail, and frail was 79.5, 16.4, and 4.1% among 3988 participants at baseline, which changed to 68.2, 23.0, and 8.8% after 2 years with 127 deaths and 23 dropped out. Twelve kinds of transitions from the three frailty statuses at baseline to four outcomes at follow-up (including death) significantly differed within each of gender and age group, as well between genders and age groups. Among these, 7.8% of prefrail or frail elders improved, 70.0% retained their frailty status, and 22.2% of robust or prefrail elders worsened in frailty status. In multivariable models, age was significantly associated with changes in frailty except for in the frail group; higher educational level and working predicted a lower risk of robust worsening. Of the lifestyle predictors, no shower facilities at home predicted a higher risk of robust worsening; more frequent physical exercise predicted a lower risk of robust worsening and a higher chance of frailty improvement; more frequent neighbor interaction predicted a lower risk of robust worsening and prefrail worsening; and more frequent social participation predicted a higher chance of prefrail improvement. Conclusions The status of frailty was reversible among community-dwelling elderly, and sociodemographic and lifestyle factors were related to changes in frailty. These findings help health practitioners to recognize susceptible individuals in a community and provide health promotional planning to target aged populations.

Christianson syndrome (CS) is an X-linked neurodevelopmental syndrome characterized by microcephaly, epilepsy, ataxia, and severe generalized developmental delay. Pathogenic mutations in the SLC9A6 gene, which encodes the Na+/H+ exchanger protein member 6 (NHE6), are associated with CS and autism spectrum disorder in males. In this study, whole exome sequencing (WES) and Sanger sequencing revealed a novel de novo frameshift variant c.1548_1549insT of SLC9A6 in a 14-month-old boy with early-onset seizures. According to The American College of Medical Genetics and Genomics (ACMG)/the Association for Molecular Pathology (AMP) guidelines, the variant was classified as pathogenic. The proband presented with several core symptoms of typical epilepsy, including microcephaly, motor delay, distal muscle weakness, micrognathia, occasional unprovoked laughter, swallowing and speech difficulties. Electroencephalography (EEG) showed spikes-slow waves in frontal pole, frontal, anterior temporal and frontal midline point areas. Gesell development schedules (GDS) indicated generalized developmental delay. We also summarized all the reported variants and analyzed the correlation of genotype and phenotype of CS. Our study extends the mutation spectrum of the SLC9A6 gene, and it might imply that the phenotypes of CS are not correlated with SLC9A6 genotypes.

Background: We aimed to evaluate the predictive value of the 'Timed Up and Go' test (TUGT) for identifying fall risk in community-dwelling elderly. Methods: From Aug 2016 to Feb 2017, cluster sampling was conducted among residents aged over 60 from 15 communities in Songjiang district, Shanghai. Face-to-face questionnaire interviews and TUGT measures were conducted to collect data. Results: 6,014 participants were enrolled, with an average age 72.7±7.0 years. 637 (10.6%) elderly people had a fall experience in the past year. TUGT for the non-fall group, one-fall group and recurrent-fall group was 9.02±4.39, 10.00±5.26 and 10.78±4.51 seconds respectively (P

Human milk oligosaccharides (HMOs) exhibit various biological activities for infants, such as serving as prebiotics, blocking pathogens, and aiding in brain development. HMOs are a complex mixture of hetero-oligosaccharides that are generally highly branched, containing multiple structural isomers and no intrinsic chromophores, presenting a challenge to both their resolution and quantitative detection. While liquid chromatography-mass spectrometry (LC-MS) has become the primary strategy for analysis of various compounds, the very polar and chromophore-free properties of native glycans hinder their separation in LC and ionization in MS. Various labeling approaches have been developed to achieve separation of glycans with higher resolution and greater sensitivity of detection. Here, we compared five commonly used labeling techniques [by 2-aminobenzamide, 2-aminopyridine, 2-aminobenzoic acid (2-AA), 2,6-diaminopyridine, and 1-phenyl-3-methyl-5-pyrazolone] for analyzing HMOs specifically under hydrophilic-interaction chromatography-mass spectrometry (HILIC-MS) conditions. The 2-AA labeling showed the most consistent deprotonated molecular ions, the enhanced sensitivity with the least structural selectivity, and the sequencing-informative tandem MS fragmentation spectra for the widest range of HMOs; therefore, this labeling technique was selected for further optimization under the porous graphitized carbon chromatography-mass spectrometry (PGC-MS) conditions. The combination strategy of 2-AA labeling and PGC-MS techniques provided online decontamination (removal of excess 2-AA, salts, and lactose) and resolute detection of many HMOs, enabling us to characterize the profiles of complicated HMO mixtures comprehensively in a simple protocol.

Abstract Background Tobacco smoking is a recognized risk factor for many chronic diseases and previous study evidences have indicated that smokers receive smoking cessation service after the diagnosis of chronic diseases increases successful rate in quitting. But the prevalence of tobacco related chronic diseases (TCD) among smokers, as well as the role of TCD diagnosis in smoking cessation is still unclear in China. Methods From June 2016 to December 2017, we sampled 36, 698 residents aged over 18 years by a three stage sampling in Songjiang district, Shanghai. We conducted a cross-sectional study to understand the prevalence of TCD among smokers, and the role of TCD diagnosis in smoking cessation among ex-smokers as well as the smoking cessation attempt among current smokers. Results Over all, the prevalence of current smoking is 19.78% (48.36% for male and 0.22% for female). 15.93% of smokers have stopped smoking successfully (1, 376/8, 636). The prevalence of ten selected TCDs among smokers range from 0.63% (Chronic Obstructive Pulmonary Disease, COPD) to 36.31% (hypertension). All of 1, 376 ex-smokers had at least one kind of TCD, and 52.33% of them stop smoking after the diagnosis of TCD, the time interval between TCD diagnosis and smoking cessation ranges from 0 to 65 years, with a median of 9 years. Smokers with TCD had higher prevalence of quit smoking, and current smokers with TCD had higher smoking cessation attempt proportion. Conclusions The prevalence of current smoking is still very high among male residents in rural area of Shanghai, and the occurrence of TCD even non-lethal one could provide an opportunity for doctors to assist the smoking cessation among smokers.

AbstractThe present systematic review and meta-analysis was undertaken to evaluate the effects of acupuncture in women with breast cancer (BC), focusing on patient-reported outcomes (PROs).MethodsA comprehensive literature search was carried out for randomized controlled trials (RCTs) reporting PROs in BC patients with treatment-related symptoms after undergoing acupuncture for at least four weeks. Literature screening, data extraction, and risk bias assessment were independently carried out by two researchers.ResultsOut of the 2, 524 identified studies, 29 studies representing 33 articles were included in this meta-analysis. At the end of treatment (EOT), the acupuncture patients’ quality of life (QoL) was measured by the QLQ-C30 QoL subscale, the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES), the Functional Assessment of Cancer Therapy–General/Breast (FACT-G/B), and the Menopause-Specific Quality of Life Questionnaire (MENQOL), which depicted a significant improvement. The use of acupuncture in BC patients lead to a considerable reduction in the scores of all subscales of the Brief Pain Inventory-Short Form (BPI-SF) and Visual Analog Scale (VAS) measuring pain. Moreover, patients treated with acupuncture were more likely to experience improvements in hot flashes scores, fatigue, sleep disturbance, and anxiety compared to those in the control group, while the improvements in depression were comparable across both groups. Long-term follow-up results were similar to the EOT results.ConclusionsCurrent evidence suggests that acupuncture might improve BC treatment-related symptoms measured with PROs including QoL, pain, fatigue, hot flashes, sleep disturbance and anxiety. However, a number of included studies report limited amounts of certain subgroup settings, thus more rigorous, well-designed and larger RCTs are needed to confirm our results.

Abstract Background Congenital hydrocephalus‐3 with brain anomalies (HYC3, MIM 617967) is a rare form of congenital hydrocephalus characterized by severe hydrocephalus and cerebellar abnormalities, the onset of the disease occurs in utero even resulting in fetal death. A very limited spectrum of WDR81 pathogenic variants had been reported in three unrelated families with HYC3. This study aims at presenting novel compound heterozygous frameshift variants in WDR81 in a Chinese fetus. Methods Whole‐exome sequencing (WES) was performed for a fetus with multiple congenital anomalies including sever hydrocephalus, cleft lip and palate, hydrops fetalis, hepatomegaly, and cerebellar hypoplasia. Sanger sequencing was performed to confirm the origin of the variants subsequently. Variants classification was based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. Results Two novel heterozygous variants c.146_147insG (p.Thr52fs) and c.673delC (p.Leu225fs) in WDR81 were identified. Sanger sequencing revealed that the c.146_147insG mutation was maternal origin and the c.673delC mutation was paternal origin. Both variants were pathogenic according to the ACMG/AMP guidelines. Conclusion The present study expands the mutation spectrum of WDR81 and help further define the genotype–phenotype correlations of HYC3. WDR81‐related HYC3 were highly clinical heterogeneity. We suggested that fetal hydrocephalus with extracerebral manifestations may be suggestive of WDR81 deficiency and WES is effective for achieving a conclusive diagnosis for disorder.

Abstract Background Liver failure caused by TRMU is a rare hereditary disorder and clinically manifests into metabolic acidosis, hyperlactatemia, and hypoglycemia. Limited spectrum of TRMU pathogenic variants has been reported. Methods Whole‐exome sequencing was employed for the diagnosis of a 5‐day‐old female who suffered from severe neonatal hyperlactatemia and hypoglycemia since birth. Sanger sequencing was performed to confirm the origin of the variants subsequently. Variants classification was followed to ACMG guideline. Results A compound heterozygosity of a frameshiftc.34_35dupTC (p.Gly13fs) and a missense c.244T>G (p.Phe82Val) in TRMU was detected, both variants are novel and pathogenic. Analysis of clinical and genetic information including patients reported previously indicated that there is no significant correlation between the genotype and the phenotype of TRMU‐caused liver failure. Conclusion To the best of our knowledge, this is the first case report of TRMU‐caused liver failure in China. Whole‐exome sequencing is effective for conclusive diagnosis of this disorder and beneficial for its clinical management.

CHARGE syndrome is a life-threatening disease caused by mutations of chromodomain helicase DNA-binding protein 7 gene (CHD7). The disease is characterized by a pattern of congenital anomalies that involve multiple organs. In this study, five patients were diagnosed as CHARGE syndrome with CHD7 mutations by whole exome sequencing. Although the clinical phenotypes of probands are highly variable and typical symptoms such as coloboma and choanal atresia are not commonly manifested in this cohort, they all presented congenital heart defects. Of note, dyspnea is the most prominent symptom in all five neonatal patients, suggesting that dyspnea might be a phenotypic clue of CHARGE syndrome.

Abstract Background A very limited spectrum of ASCC1 pathogenic variants had been reported in six (mostly consanguineous) families with spinal muscular atrophy with congenital bone fractures 2 [OMIM #616867] since 2016. Methods A proband from a non‐consanguineous Chinese family presented with neonatal severe hypotonia, respiratory distress, muscle weakness, and atrophy, as well as congenital bone fractures was performed by exome sequencing. Results A compound heterozygosity of a nonsense (c.932C>G,p.Ser311Ter) and an exon 5 deletion in ASCC1 segregating with phenotypes was detected, both variants are novel and pathogenic. Since ASCC1 is a relatively new disease gene, we performed the gene curation by ClinGen SOP. The existing evidence is sufficient to support a "Definitive" level of disease‐gene relationship. Conclusion This case report expended the mutation spectrum of ASCC1 and support the notion that this novel disease also occurs in outbreed populations and this is a rare disease but may still be underdiagnosed due to its perinatal lethal outcomes.