Clinical and genetic risk factors underlying severe consequence identified in 75 families with unilateral high myopia.

BACKGROUNDS: Unilateral high myopia (uHM), commonly observed in patients with retinal diseases or only with high myopia, is frequently associated with amblyopia with poor prognosis. This study aims to reveal the clinical and genetic spectrum of uHM in a large Chinese cohort. METHODS: A total of 75 probands with simplex uHM were included in our Pediatric and Genetic Eye Clinic. Patients with significant posterior anomalies other than myopic fundus changes were excluded. Variants were detected by exome sequencing and then analyzed through multiple-step bioinformatic and co-segregation analysis and finally confirmed by Sanger sequencing. Genetic findings were correlated with associated clinical data for analysis. RESULTS: Among the 75 probands with a mean age of 6.21 ± 4.70 years at the presentation, myopic fundus of C1 and C2 was observed in 73 (97.3%) probands. Surprisingly, specific peripheral changes were identified in 63 eyes involving 36 (48.0%) probands after extensive examination, including peripheral retinal avascular zone (74.6%, 47/63 eyes), neovascularization (54.0%), fluorescein leakage (31.7%), peripheral pigmentary changes (31.7%), and others. Exome sequencing identified 21 potential pathogenic variants of 13 genes in 20 of 75 (26.7%) probands, including genes for Stickler syndrome (COL11A1 and COL2A1; 6/20), FEVR (FZD4, LRP5, and TSPAN12; 5/20), and others (FBN1, GPR179, ZEB2, PAX6, GPR143, OPN1LW, FRMD7, and CACNA1F; 9/20). For the peripheral retinal changes in the 20 probands, variants in Stickler syndrome-related genes were predominantly associated with retinal pigmentary changes, lattice degeneration, and retinal avascular region, while variants in genes related to FEVR were mainly associated with the avascular zone, neovascularization, and fluorescein leakage. CONCLUSIONS: Genetic defects were identified in about one-fourth of simplex uHM patients in which significant consequences may be hidden under a classic myopic fundus in up to half. To our knowledge, this is the first systematic genetic study on simplex uHM to date. In addition to routine care of strabismus and amblyopia, careful examination of the peripheral retina and genetic screening is warranted for patients with uHM in order to identify signs of risk for retinal detachment and other complications and provide meaningful genetic counseling.

Development of a prediction model for predicting the prevalence of nonalcoholic fatty liver disease in Chinese nurses: the first-year follow data of a web-based ambispective cohort study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is gradually becoming a huge threat to public health. With complex working characteristics, female nurses had been found with high risk of NAFLD. To develop and validate a prediction model to predict the prevalence of NAFLD based on demographic characteristics, work situation, daily lifestyle and laboratory tests in female nurses. METHODS: This study was a part of the Chinese Nurse Cohort Study (The National Nurse Health Study, NNHS), and data were extracted from the first-year follow data collected from 1st June to 1st September 2021 by questionnaires and physical examination records in a comprehensive tertiary hospital. The questionnaires included demographic characteristics, work situation and daily lifestyle. Logistic regression and a nomogram were used to develop and validate the prediction model. RESULTS: A total of 824 female nurses were included in this study. Living situation, smoking history, monthly night shift, daily sleep time, ALT/AST, FBG, TG, HDL-C, UA, BMI, TBil and Ca were independent risk factors for NAFLD occurance. A prediction model for predicting the prevalence of NAFLD among female nurses was developed and verified in this study. CONCLUSION: Living situation, smoking history, monthly night shift, daily sleep time, ALT/AST, FBG, TG, UA, BMI and Ca were independent predictors, while HDL-C and Tbil were independent protective indicators of NAFLD occurance. The prediction model and nomogram could be applied to predict the prevalence of NAFLD among female nurses, which could be used in health improvement. TRIAL REGISTRATION: This study was a part of the Chinese Nurse Cohort Study (The National Nurse Health Study, NNHS), which was a ambispective cohort study contained past data and registered at Clinicaltrials.gov ( https://clinicaltrials.gov/ct2/show/NCT04572347 ) and the China Cohort Consortium ( http://chinacohort.bjmu.edu.cn/project/102/ ).

Hypoxia preconditioning of adipose stem cell-derived exosomes loaded in gelatin methacryloyl (GelMA) promote type H angiogenesis and osteoporotic fracture repair.

The challenges posed by delayed atrophic healing and nonunion stand as formidable obstacles in osteoporotic fracture treatment. The processes of type H angiogenesis and osteogenesis emerge as pivotal mechanisms during bone regeneration. Notably, the preconditioning of adipose-derived stem cell (ADSC) exosomes under hypoxic conditions has garnered attention for its potential to augment the secretion and functionality of these exosomes. In the present investigation, we embarked upon a comprehensive elucidation of the underlying mechanisms of hypo-ADSC-Exos within the milieu of osteoporotic bone regeneration. Our findings revealed that hypo-ADSC-Exos harboured a preeminent miRNA, namely, miR-21-5p, which emerged as the principal orchestrator of angiogenic effects. Through in vitro experiments, we demonstrated the capacity of hypo-ADSC-Exos to stimulate the proliferation, migration, and angiogenic potential of human umbilical vein endothelial cells (HUVECs) via the mediation of miR-21-5p. The inhibition of miR-21-5p effectively attenuated the proangiogenic effects mediated by hypo-ADSC-Exos. Mechanistically, our investigation revealed that exosomal miR-21-5p emanating from hypo-ADSCs exerts its regulatory influence by targeting sprouly1 (SPRY1) within HUVECs, thereby facilitating the activation of the PI3K/AKT signalling pathway. Notably, knockdown of SPRY1 in HUVECs was found to potentiate PI3K/AKT activation and, concomitantly, HUVEC proliferation, migration, and angiogenesis. The culminating stage of our study involved a compelling in vivo demonstration wherein GelMA loaded with hypo-ADSC-Exos was validated to substantially enhance local type H angiogenesis and concomitant bone regeneration. This enhancement was unequivocally attributed to the exosomal modulation of SPRY1. In summary, our investigation offers a pioneering perspective on the potential utility of hypo-ADSC-Exos as readily available for osteoporotic fracture treatment.

Relationship between night shift and sleep problems, risk of metabolic abnormalities of nurses: a 2 years follow-up retrospective analysis in the National Nurse Health Study (NNHS).

BACKGROUND AND PURPOSE: Efforts to improve nurses' physical and mental health are critical to ensuring the safety and quality of the healthcare system. Long-term studies targeting the relevancy of nurses' occupation characteristics with health conditions remain insufficient. This study aimed to examine the relationship between nurses' night shift and sleep problems and metabolic abnormalities risk. METHODS: This study was a part of the National Nurse Health Study, an ambispective cohort study in China, in 2021. Based on an integration physical examination data system, this study carried out a retrospective analysis of 730 nurses from 2018 to 2020 and combined with a questionnaire survey in 2021. The STROBE guidelines were adopted for reporting. RESULTS: In the 23 (23.0, 24.0) months follow-up, higher night shift load was associated with more sleep problems such as shortened sleep duration, sleep disorders, poor sleep quality, and sleep deprivation. Moreover, night shift load was associated with chronic diseases risk factors, increasing body mass index and body fat, with more night shift density, increasing the occurrence of low levels of high-density lipoprotein cholesterol, high triglyceride, triglyceride/high-density lipoprotein cholesterol ratio, and serum uric acid. CONCLUSION: The night shift load has become an occupational health concern, contributing to chronic diseases relevant metabolic risk factors and negative influence on sleep health. Focus on the strategies to improve the sleep quality of nurses undergoing night shift work, optimize work scheduling and ongoing monitor the relevant risk factors are essential to enhance the stability and well-being of the nursing workforce. CLINICAL TRIALS REGISTRATION INFORMATION: NCT04572347, on October 1, 2020. https://www. CLINICALTRIALS: gov/ct2/show/NCT04572347.

Defect of TIMP4 Is Associated with High Myopia and Participates in Rat Ocular Development in a Dose-Dependent Manner.

Thinning of the sclera happens in myopia eyes owing to extracellular matrix (ECM) remodeling, but the initiators of the ECM remodeling in myopia are mainly unknown. The matrix metalloproteinase (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs) regulate the homeostasis of the ECM. However, genetic studies of the MMPs and TIMPs in the occurrence of myopia are poor and limited. This study systematically investigated the association between twenty-nine genes of the TIMPs and MMPs families and early-onset high myopia (eoHM) based on whole exome sequencing data. Two TIMP4 heterozygous loss-of-function (LoF) variants, c.528C>A in six patients and c.234_235insAA in one patient, were statistically enriched in 928 eoHM probands compared to that in 5469 non-high myopia control (p = 3.7 × 10-5) and that in the general population (p = 2.78 × 10-9). Consequently, the Timp4 gene editing rat was further evaluated to explore the possible role of Timp4 on ocular and myopia development. A series of ocular morphology abnormalities in a dose-dependent manner (Timp4-/- < Timp4+/- < Timp4+/+) were observed in a rat model, including the decline in the retinal thickness, the elongation in the axial length, more vulnerable to the form deprivation model, morphology changes in sclera collagen bundles, and the decrease in collagen contents of the sclera and retina. Electroretinogram revealed that the b-wave amplitudes of Timp4 defect rats were significantly reduced, consistent with the shorter length of the bipolar axons detected by HE and IF staining. Heterozygous LoF variants in the TIMP4 are associated with early onset high myopia, and the Timp4 defect disturbs ocular development by influencing the morphology and function of the ocular tissue.

Variant Landscape of 15 Genes Involved in Corneal Dystrophies: Report of 30 Families and Comprehensive Analysis of the Literature.

Corneal dystrophies (CDs) represent a group of inherited diseases characterized by the progressive deposit of abnormal materials in the cornea. This study aimed to describe the variant landscape of 15 genes responsible for CDs based on a cohort of Chinese families and a comparative analysis of literature reports. Families with CDs were recruited from our eye clinic. Their genomic DNA was analyzed using exome sequencing. The detected variants were filtered using multi-step bioinformatics and confirmed using Sanger sequencing. Previously reported variants in the literature were summarized and evaluated based on the gnomAD database and in-house exome data. In 30 of 37 families with CDs, 17 pathogenic or likely pathogenic variants were detected in 4 of the 15 genes, including TGFBI, CHST6, SLC4A11, and ZEB1. A comparative analysis of large datasets revealed that 12 of the 586 reported variants are unlikely causative of CDs in monogenic mode, accounting for 61 of 2933 families in the literature. Of the 15 genes, the gene most frequently implicated in CDs was TGFBI (1823/2902, 62.82% of families), followed by CHST6 (483/2902, 16.64%) and SLC4A11 (201/2902, 6.93%). This study presents, for the first time, the landscape of pathogenic and likely pathogenic variants in the 15 genes responsible for CDs. Awareness of frequently misinterpreted variants, such as c.1501C>A, p.(Pro501Thr) in TGFBI, is crucial in the era of genomic medicine.

New Insight into the Genotype-Phenotype Correlation of PRPH2-Related Diseases Based on a Large Chinese Cohort and Literature Review.

Variants in PRPH2 are a common cause of inherited retinal dystrophies with high genetic and phenotypic heterogeneity. In this study, variants in PRPH2 were selected from in-house exome sequencing data, and all reported PRPH2 variants were evaluated with the assistance of online prediction tools and the comparative validation of large datasets. All variants were classified based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. Individuals with pathogenic or likely pathogenic variants of PRPH2 were confirmed by Sanger sequencing. Clinical characteristics were summarized. Ten pathogenic or likely pathogenic variants of PRPH2 were identified in 14 families. In our cohort, the most frequent variant was p.G305Afs*19, accounting for 33.3% (5/15) of alleles, in contrast to the literature, where p.R172G (11.6%, 119/1028) was the most common variant. Nine in-house families (63.8%) were diagnosed with retinitis pigmentosa (RP), distinct from the phenotypic spectrum in the literature, which shows that RP accounts for 27.9% (283/1013) and macular degeneration is more common (45.2%, 458/1013). Patients carrying missense variants predicted as damaging by all seven prediction tools and absent in the gnomAD database were more likely to develop RP compared to those carrying missense variants predicted as damaging with fewer tools or with more than one allele number in the gnomAD database (p = 0.001). The population-specific genetic and phenotypic spectra of PRPH2 were explored, and novel insight into the genotype-phenotype correlation of PRPH2 was proposed. These findings demonstrated the importance of assessing PRPH2 variants in distinct populations and the value of providing practical suggestions for the genetic interpretation of PRPH2 variants.

Effectiveness of chlorhexidine versus povidone-iodine for preventing surgical site wound infection: A meta-analysis.

A systematic evaluation was conducted to assess the efficacy of two disinfectants, chlorhexidine and povidone-iodine, as primary components in preventing surgical site infection (SSI). A comprehensive computerised search was performed in the PubMed, EMBASE, Web of Science, Cochrane Library, CNKI and Wanfang databases for randomised controlled trials (RCTs) on chlorhexidine and povidone-iodine disinfection for the prevention of SSI from inception until July 2023. Two independent researchers completed literature screening, data extraction and quality assessment of the included studies. The meta-analysis was conducted using RevMan 5.4 software. Ultimately, 20 RCTs were included, which included 13 133 patients, with 6460 patients in the chlorhexidine group and 6673 patients in the povidone-iodine group. The meta-analysis results revealed that the incidence rate of surgical site wound infections [odds ratio (OR): 0.67, 95% confidence interval (CI): 0.58-0.78, p < 0.001)], superficial SSI rate (OR: 0.59, 95% CI: 0.46-0.75, p < 0.001) and deep SSI rate (OR: 0.49, 95% CI: 0.31-0.79, p = 0.003) were all lower in patients subjected to chlorhexidine disinfection compared to those patients receiving povidone-iodine disinfection. Existing evidence suggests that chlorhexidine is more effective than povidone-iodine at preventing SSI. However, owing to the potential quality limitations of the included studies, further validation through high-quality large-scale RCTs is warranted.

Genetic and clinical features of BEST1-associated retinopathy based on 59 Chinese families and database comparisons.

Variants in BEST1 are one of the most common cause of retinopathy mainly involving the retinal pigment epithelium with both dominant and recessive traits. This study aimed to describe the characteristics of potential pathogenic variants (PPVs) in BEST1 and their associated clinical features. Variants in BEST1 were collected from our in-house exome sequencing data and systematically evaluated by in silico prediction tools as well as genotype-phenotype analysis. The pathogenicity features of the BEST1 variants were further assessed through database comparison among the in-house data, Genome Aggregation Database from the general population, and all previously published literature. The clinical information of the in-house patients was summarized. The PPVs in BEST1 were identified in 66 patients from 59 families, including 32 families with Best vitelliform macular dystrophy (BVMD) and 27 families with autosomal recessive bestrophinopathy (ARB). These PPVs included 31 missense variants, seven truncation variants, one in-frame deletion, and a known 3-untranslated region variant. All the truncations detected in our study were exclusively involved in ARB but not BVMD. Among the 31 missense variants, 18 missenses associated with BVMD in the dominant trait were clustered in four hotspot regions with statistically significant differences from the recessive missenses. Except for distinct macular changes, there were no statistically significant differences among the other associated clinical features between BVMD and ARB, including peripheral retinopathy, high hyperopia, and angle-closure glaucoma. In conclusion, BEST1-associated dominant retinopathy was preferentially caused by missense variants located in important functional regions. Truncations were most likely benign in heterozygous status. Future studies are expected to elucidate the mystery of the same missense variants contributing to both BVMD and ARB.

CPSF1 mutations are associated with early-onset high myopia and involved in retinal ganglion cell axon projection.

High myopia is a severe form of nearsightedness, which can result in blindness due to its associated complications. While both genetic and environmental factors can cause high myopia, early-onset high myopia (eoHM), which is defined as high myopia that occurs before school age, is considered to be caused mainly by genetic variations, with minimal environmental involvement. Here we report six rare heterozygous loss-of-function (LoF) variants in CPSF1 that were identified in six of 623 probands with eoHM but none of 2657 probands with other forms of genetic eye diseases; this difference was statistically significant (P = 4.60 × 10-5, Fisher's exact test). The six variants, which were confirmed by Sanger sequencing, were c.3862_3871dup (p.F1291*), c.2823_2824del (p.V943Lfs*65), c.1858C>T (p.Q620*), c.15C>G (p.Y5*), c.3823G>T (p.D1275Y) and c.4146-2A>G. Five of these six variants were absent in existing databases, including gnomAD, 1000G and EVS. The remaining variant, c.4146-2A>G, was present in gnomAD with a frequency of 1/229918. Clinical data demonstrated eoHM in the six probands with these mutations. Knockdown of cpsf1 by morpholino oligonucleotide (MO) injection in zebrafish eggs resulted in small eye size in 84.38% of the injected larvae, and this phenotype was rescued in 61.39% of the zebrafish eggs when the cpsf1 MO and the cpsf1 mRNA were co-injected. The projection of retinal ganglion cell (RGC) towards the tectum was abnormal in cpsf1 morphants. Thus, we demonstrated that heterozygous LoF mutations in CPSF1 are associated with eoHM and that CPSF1 may play an important role in the development of RGC axon projection.

Pathogenicity evaluation and the genotype-phenotype analysis of OPA1 variants.

Autosomal dominant optic atrophy (ADOA) is an important cause of irreversible visual impairment in children and adolescents. About 60-90% of ADOA is caused by the pathogenic variants of OPA1 gene. By evaluating the pathogenicity of OPA1 variants and summarizing the relationship between the genotype and phenotype, this study aimed to provide a reference for clinical genetic test involving OPA1. Variants in OPA1 were selected from the exome sequencing results in 7092 cases of hereditary eye diseases and control groups from our in-house data. At the same time, the urine cells of some optic atrophy patients with OPA1 variants as well as their family members were collected and oxygen consumption rates (OCR) were measured in these cells to evaluate the pathogenicity of variants. As a result, 97 variants were detected, including 94 rare variants and 3 polymorphisms. And the 94 rare variants were classified into three groups: pathogenic (33), variants of uncertain significance (19), and likely benign (42). Our results indicated that the frameshift variants at the 3' terminus might be pathogenic, while the variants in exon 7 and intron 4 might be benign. The penetrance of the missense variants was higher than that of truncation variants. The OCR of cells with pathogenic OPA1 variants were significantly lower than those without pathogenic variants. In conclusion, some variants might be benign although predicted pathogenic in previous studies while some might have unknown pathogenesis. Measuring the OCR in urine cells could be used as a method to evaluate the pathogenicity of some OPA1 variants.

Spectrum-frequency and genotype-phenotype analysis of rhodopsin variants.

Mutations in RHO are the most common cause of autosomal dominant retinitis pigmentosa. However, the pathogenicity of many RHO variants is questionable. This study was designed to investigate the genotype-phenotype correlation for RHO variants. These RHO variants were collected from the in-house exome sequencing data of 7092 probands suffering from different types of eye conditions. The variants were classified using bioinformatics tools, family segregation, and clinical phenotypes. The RHO variants were assessed using multiple online tools and a genotype-phenotype analysis based on the data collected from of ours, gnomAD, and published literature. Totally, 52 heterozygous variants of RHO were detected in the 7092 probands. Of these 52, 17 were potentially pathogenic, were present in 35 families, and comprised 15 missense variants, one inframe deletion and one nonsense variant. All the 15 missense variants were predicted to be damaging by five different online tools. The analysis of the clinical data of the patients from the 35 families revealed certain common features, of an early damage to both the rods and the cones, relatively preserved visual acuity in adulthood, and mid-peripheral tapetoretinal degeneration with pigmentation or RPE atrophy. Our data, the data from gnomAD, and the systematic review of the 246 previously reported variants suggest that approximately two-thirds of the rare missense variants and most of the truncated variants involving upstream of K296 are likely benign. This study provides a brief summary of the characteristics of the pathogenic RHO variants. It emphasizes that the systematic evaluation of these variants at the individual-gene level is crucial in the current era of clinical genetic testing even for a well-known gene such as RHO.

Novel variants in GUCY2D causing retinopathy and the genotype-phenotype correlation.

Leber congenital amaurosis (LCA) is the most severe form of retinopathy and cone/cone-rod dystrophy (CORD) is a common form of inherited retinopathy. Variants in GUCY2D constitute the most common cause of LCA and autosomal dominant CORD (ADCORD). The purpose of this study was to reveal novel variants and document associated phenotypes of patients with GUCY2D-associated retinopathy. Fifty-two potentially pathogenic variants (PPVs), including 12 novel ones (p.Gly144_Ala164del, p.Trp154Glyfs*12, p.Leu186Pro, p.Ala207Pro, p.Ala229Asp, p.Ala353Glu, p.Trp372*, p.Arg528*, p.Arg660Pro, p.Ile682Thr, p.Trp788Cys, and c.1026 + 171_*486del), were identified in 16 families with ADCORD and 34 families with autosomal recessive LCA (ARLCA). The novel variant c.1026 + 171_*486del is a large-scale (16.3 kb) deletion involving exons 4-20 of GUCY2D, and was identified in an ARLCA family in heterozygous status mimicking a homozygous p.Trp788Cys variant. Among the detected 52 PPVs, 32 (61.5%) were missense, seven (13.5%) were splicing, six (11.5%) were nonsense, four (7.7%) were inframe indel, and three (5.8%) were frameshift deletion. The median age of examination in 27 patients with ADCORD was 21.0 years (ranges 3-54) with a median visual acuity (VA) of 0.10 (ranges 0.02-0.90). There were 48.0% of patients with macular atrophy, 86.4% with severe reduced or extinguished cone responses, 77.3% with normal or mildly reduced rod responses, and 60.9% with high myopia. Visual impairment, macular dystrophy, and cone dysfunction deteriorated with age. The median age of examination in 34 patients with ARLCA was 1.1 years (ranges 0.3-25). There were 55.9% of patients with roving nystagmus, 68.2% with VA of worse than hand motion, 59.4% with almost normal fundus, 90.6% with extinguished rod and cone responses, and 50.0% with high hyperopia. In conclusions, twelve novel PPVs in GUCY2D (including a novel large-scale deletion) were identified. Most (32/52, 61.5%) of causative GUCY2D variants were missense. Progressive development of macular atrophy, cone dysfunction, visual impairment, and myopia are four major characteristics of GUCY2D-associated ADCORD. Normal fundus, roving nystagmus, and hypermetropia in early age are common findings specific to GUCY2D-associated ARLCA. The obtained data in this study will be of value in counselling patients and designing future therapeutic approaches.

MicroRNA-139-5p Promotes Functional Recovery and Reduces Pain Hypersensitivity in Mice with Spinal Cord Injury by Targeting Mammalian Sterile 20-like Kinase 1.

Currently, there is no cure for spinal cord injury (SCI), a heavy burden on patients physiology and psychology. We found that microRNA-139-5p (miR-139-5p) expression was significantly downregulated in damaged spinal cords in mice. So, we aimed to test the effect of treatment with miR-139-5p on functional recovery and neuropathic pain in mice with SCI and investigate the underlying mechanism. The luciferase reporter assay revealed that miR-139-5p directly targeted mammalian sterile 20-like kinase 1 (Mst1), and miR-139-5p treatment suppressed Mst1 protein expression in damaged spinal cords of mice. Wild-type mice and Mst1(-/-) mice were exposed to SCI and treated with miR-139-5p agomir via intrathecal infusion. Treatment of SCI mice with miR-139-5p accelerated locomotor functional recovery, reduced hypersensitivities to mechanical and thermal stimulations, and promoted neuronal survival in damaged spinal cords. Treatment with miR-139-5p enhanced phosphorylation of adenosine monophosphate-activated protein kinase alpha (AMPKα), improved mitochondrial function, and suppressed NF-κB-related inflammation in damaged spinal cords. Deficiency of Mst1 had similar benefits in mice with SCI. Furthermore, miR-139-5p treatment did not provide further protection in Mst1(-/-) mice against SCI. In conclusion, miR-139-5p treatment enhanced functional recovery and reduced pain hypersensitivity in mice with SCI, possibly through targeting Mst1.

Pathogenic variants and associated phenotypic spectrum of TSPAN12 based on data from a large cohort.

PURPOSE: The pathogenic variants in TSPAN12 could lead to familial exudative vitreoretinopathy (FEVR), which has high clinical variability. This study aims to assess the pathogenicity of TSPAN12 variants and their phenotypic spectrum based on exome sequencing from 7092 probands with different eye conditions. METHODS: The variants in TSPAN12 were selected from exome sequencing data of samples from 7092 probands with different forms of eye conditions. Potentially pathogenic variants were evaluated through the annotation of types, locations, population frequencies, and in silico predictions of variants from in-house data, gnomAD, and published literature. The clinical features of patients with potentially pathogenic variants in TSPAN12 were assessed. RESULTS: A total of 45 variants in TSPAN12 with coding effects were detected based on the exome data from 7092 probands, among which 31 were classified as pathogenic variants including 15 novels. The 31 variants were identified in 34 probands with various initial diagnoses, including FEVR in 21 probands and diseases other than FEVR in the remaining 13 probands. Biallelic pathogenic variants were identified in one proband with initial diagnosis of high myopia. CONCLUSION: Truncating variants and the missense variants that are predicted as deleterious are likely pathogenic variants of TSPAN12. Approximately 61.8% of patients with pathogenic variants in this gene had an initial diagnosis of FEVR, and the remaining 38.2% of patients had various initial diagnoses. These findings expand the understanding about variant evaluation of TSPAN12 and phenotypic spectrum of TSPAN12-associated FEVR.

Influence of low-molecular-weight heparin injection sites on local bruising and pain: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Subcutaneous administration of low-molecular-weight heparin (LMWH) may cause complications such as haematoma, bruising and pain at different injection sites. Several studies have been carried out to investigate whether bruising and pain depend on injection sites; however, the results have been conflicting, and a clear consistent conclusion has not been reached. The purpose of this systematic review and meta-analysis was to assess the incidence and severity of bruising and pain after subcutaneous injection of LMWH in different sites. METHODS: Two reviewers independently searched the Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure (CNKI) databases for randomized controlled and self-controlled trials reporting side-effects from LMWH with different subcutaneous injection sites. Cochrane bias risk assessment tools and the Newcastle-Ottawa Scale (NOS) were used to evaluate the quality of the randomized controlled and self-controlled trials, respectively. Rev Man 5.3 software was used to analyse the data that were extracted after quality assessment to determine the incidence and severity of side-effects at different subcutaneous injection sites. RESULTS AND DISCUSSION: A total of eleven studies were included in this analysis. The meta-analysis provided evidence that subcutaneous injection in the abdominal area had a lower incidence of bruising than that in the arm area (risk ratios: 0.76; 95% confidence interval: 0.64-0.90; I2  = 52%, p < .05), but the difference in the bruising size between the two injection sites was marginally significant (standardized mean difference: 0.08; 95% confidence interval: -0.45 to 0.62; I2  = 85%, p > .05). There was also no significant difference in the bruising size between subcutaneous injection in the abdominal area and subcutaneous injection in the thigh area (standardized mean difference: -0.16; 95% confidence interval: -0.34 to 0.22; I2  = 32%, p > .05). Subcutaneous injections in the abdominal area had a lower severity of pain than injections in the arm area (risk ratios: 0.57; 95% confidence interval: 0.48-0.67; I2  = 81%; p < .05), but no statistically significant difference was shown between the pain intensity in the abdominal and arm area (mean difference: -1.64; 95% confidence interval: -4.36 to 1.08; I2  = 99%; p > .05). WHAT IS NEW AND CONCLUSION: Subcutaneous injection of LMWH in the abdominal area could reduce the incidence of side-effects at the injection site and reduce patient discomfort. The abdomen is proposed as the first choice of injection site for LMWH. The findings provide useful information to nurses in clinical practice when choosing the subcutaneous injection site for LMWH.

Structural variations in a non-coding region at 1q32.1 are responsible for the NYS7 locus in two large families.

Congenital motor nystagmus (CMN) is characterized by early-onset bilateral ocular oscillations without other ocular deficits. To date, mutations in only one gene have been identified to be responsible for CMN, i.e., FRMD7 for X-linked CMN. Four loci for autosomal dominant CMN, including NYS7 (OMIM 614826), have been mapped but the causative genes have yet to be identified. NYS7 was mapped to 1q32.1 based on independent genome-wide linkage scan on two large families with CMN. In this study, mutations in all known protein-coding genes, both intronic sequence with predicted effect and coding sequence, in the linkage interval were excluded by whole-genome sequencing. Then, long-read genome sequencing based on the Nanopore platform was performed with a sample from each of the two families. Two deletions with an overlapping region of 775,699 bp, located in a region without any known protein-coding genes, were identified in the two families in the linkage region. The two deletions as well as their breakpoints were confirmed by Sanger sequencing and co-segregated with CMN in the two families. The 775,699 bp deleted region contains uncharacterized non-protein-coding expressed sequences and pseudogenes but no protein-coding genes. However, Hi-C data predicted that the deletions span two topologically associated domains and probably lead to a change in the 3D genomic architecture. These results provide novel evidence of a strong association between structural variations in non-coding genomic regions and human hereditary diseases like CMN with a potential mechanism involving changes in 3D genome architecture, which provides clues regarding the molecular pathogenicity of CMN.

Genotypes and phenotypes of genes associated with achromatopsia: A reference for clinical genetic testing.

Purpose: Achromatopsia is a congenital autosomal recessive cone disorder, and it has been found to be associated with six genes. However, pathogenic variants in these six genes have been identified in patients with various retinal dystrophies with the exception of achromatopsia. Thus, this study aims to investigate the contribution of these genes in hereditary retinal diseases and the potential genotype-phenotype correlations. Methods: Biallelic variants in six achromatopsia-related genes, namely, CNGA3, CNGB3, GNAT2, ATF6, PDE6C, and PDE6H, were analyzed based on data obtained from 7,195 probands with different eye conditions. A systematic genotype-phenotype analysis of these genes was performed based on these data, along with the data reported in the literature. Results: Biallelic potential pathogenic variants (PPVs) in five of the six genes were identified in 119 probands with genetic eye diseases. The variants in CNGA3 were the most common and accounted for 81.5% (97/119). Of the 119 probands, 62.2% (74/119) have cone-rod dystrophy, whereas only 25.2% (30/119) have achromatopsia. No biallelic pathogenic variants in these genes were identified in patients with rod-dominant degeneration. A systematic review of genotypes and phenotypes revealed certain characteristics of each of the six genes, providing clues for the pathogenicity evaluation of the variants of the genes. Conclusions: PPVs in the six genes were identified in various inherited retinal degeneration diseases, most of which are cone-dominant diseases but no rod-dominant diseases based on the data from a cohort of 7,195 probands with different eye conditions. The systematic genotype-phenotype analysis of these genes will be useful in drafting guidelines for the clinical genetic diagnostic application for the investigated genes.

Biallelic mutations in USP45, encoding a deubiquitinating enzyme, are associated with Leber congenital amaurosis.

BACKGROUND: Leber congenital amaurosis (LCA) is the earliest and most severe form of inherited retinal dystrophies. In approximately 56% of Chinese probands, genetic defects can be detected in known LCA-causing genes. In this study, the objective was to identify pathogenic variants in two unsolved Chinese families with LCA. METHODS: To identify the genetic defect, whole-exome sequencing (WES) and clinical analysis was performed in both probands with LCA as well as in 3011 in-house controls with other hereditary eye diseases. The expression profiles, as well as the phenotype analysis of knockdown zebrafish model and knockout mice model, were performed to investigate the function of USP45 in photoreceptors. RESULTS: By analysing WES data based on allele frequencies of in-house controls, population allele frequencies and in silico prediction tools, two rare homozygous mutations in USP45 were identified in two unrelated families. Immunohistochemistry of USP45 in the human and zebrafish retinal sections revealed enriched expression in the inner segments of photoreceptors. The knockdown of usp45 transcript in zebrafish led to abnormal retinal development with effects on photoreceptors, which could be successfully rescued by wild-type usp45 mRNA. Moreover, targeted knockout of Usp45 in mice caused abnormal electroretinography responses, similar to that seen in patients with LCA. CONCLUSIONS: Our study implicates that biallelic mutations in USP45 are associated with the occurrence of LCA. Moreover, our results indicate that USP45 is indispensable to the maintenance of photoreceptor function.

Mutation profile of glaucoma candidate genes in Mauritanian families with primary congenital glaucoma.

Purpose: Intraocular pressure leading to glaucoma is a major cause of childhood blindness in developing countries. In this study, we sought to identify gene variants potentially associated with primary congenital glaucoma (PCG) in the Mauritanian population. Methods: Using next-generation sequencing (NGS), a panel of PCG candidate genes was screened in a search for DNA mutations in four families with multiple occurrences of PCG. Results: Targeted exome sequencing analysis revealed predicted pathogenic mutations in four genes: CYP1B1 (c.217_218delTC, p.Ser73Valfs*150), MYOC (878C>A, p.T293K), NTF4 (c.601T>G, p.Cys201Gly), and WDR36 (c.2078A>G, p.Asn693Ser), each carried by a different family. Conclusions: Genetic variation associated with PCG in this study reflects the ethnic heterogeneity of the Mauritanian population. However, a larger cohort is needed to identify additional families carrying these mutations and confirm their biologic role.