KCTD10 regulates brain development by destabilizing brain disorder-associated protein KCTD13.

KCTD10 belongs to the KCTD (potassiumchannel tetramerization domain) family, many members of which are associated with neuropsychiatric disorders. However, the biological function underlying the association with brain disorders remains to be explored. Here, we reveal that Kctd10 is highly expressed in neuronal progenitors and layer V neurons throughout brain development. Kctd10 deficiency triggers abnormal proliferation and differentiation of neuronal progenitors, reduced deep-layer (especially layer V) neurons, increased upper-layer neurons, and lowered brain size. Mechanistically, we screened and identified a unique KCTD10-interacting protein, KCTD13, associated with neurodevelopmental disorders. KCTD10 mediated the ubiquitination-dependent degradation of KCTD13 and KCTD10 ablation resulted in a considerable increase of KCTD13 expression in the developing cortex. KCTD13 overexpression in neuronal progenitors led to reduced proliferation and abnormal cell distribution, mirroring KCTD10 deficiency. Notably, mice with brain-specific Kctd10 knockout exhibited obvious motor deficits. This study uncovers the physiological function of KCTD10 and provides unique insights into the pathogenesis of neurodevelopmental disorders.

VarCards2: an integrated genetic and clinical database for ACMG-AMP variant-interpretation guidelines in the human whole genome.

VarCards, an online database, combines comprehensive variant- and gene-level annotation data to streamline genetic counselling for coding variants. Recognising the increasing clinical relevance of non-coding variations, there has been an accelerated development of bioinformatics tools dedicated to interpreting non-coding variations, including single-nucleotide variants and copy number variations. Regrettably, most tools remain as either locally installed databases or command-line tools dispersed across diverse online platforms. Such a landscape poses inconveniences and challenges for genetic counsellors seeking to utilise these resources without advanced bioinformatics expertise. Consequently, we developed VarCards2, which incorporates nearly nine billion artificially generated single-nucleotide variants (including those from mitochondrial DNA) and compiles vital annotation information for genetic counselling based on ACMG-AMP variant-interpretation guidelines. These annotations include (I) functional effects; (II) minor allele frequencies; (III) comprehensive function and pathogenicity predictions covering all potential variants, such as non-synonymous substitutions, non-canonical splicing variants, and non-coding variations and (IV) gene-level information. Furthermore, VarCards2 incorporates 368 820 266 documented short insertions and deletions and 2 773 555 documented copy number variations, complemented by their corresponding annotation and prediction tools. In conclusion, VarCards2, by integrating over 150 variant- and gene-level annotation sources, significantly enhances the efficiency of genetic counselling and can be freely accessed at http://www.genemed.tech/varcards2/.

Multiomics dynamic learning enables personalized diagnosis and prognosis for pancancer and cancer subtypes.

Artificial intelligence (AI) approaches in cancer analysis typically utilize a 'one-size-fits-all' methodology characterizing average patient responses. This manner neglects the diverse conditions in the pancancer and cancer subtypes of individual patients, resulting in suboptimal outcomes in diagnosis and treatment. To overcome this limitation, we shift from a blanket application of statistics to a focus on the explicit recognition of patient-specific abnormalities. Our objective is to use multiomics data to empower clinicians with personalized molecular descriptions that allow for customized diagnosis and interventions. Here, we propose a highly trustworthy multiomics learning (HTML) framework that employs multiomics self-adaptive dynamic learning to process each sample with data-dependent architectures and computational flows, ensuring personalized and trustworthy patient-centering of cancer diagnosis and prognosis. Extensive testing on a 33-type pancancer dataset and 12 cancer subtype datasets underscored the superior performance of HTML compared with static-architecture-based methods. Our findings also highlighting the potential of HTML in elucidating complex biological pathogenesis and paving the way for improved patient-specific care in cancer treatment.

Inhibiting proBDNF to mature BDNF conversion leads to ASD-like phenotypes in vivo.

Autism Spectrum Disorders (ASD) comprise a range of early age-onset neurodevelopment disorders with genetic heterogeneity. Most ASD related genes are involved in synaptic function, which is regulated by mature brain-derived neurotrophic factor (mBDNF) and its precursor proBDNF in a diametrically opposite manner: proBDNF inhibits while mBDNF potentiates synapses. Here we generated a knock-in mouse line (BDNFmet/leu) in which the conversion of proBDNF to mBDNF is attenuated. Biochemical experiments revealed residual mBDNF but excessive proBDNF in the brain. Similar to other ASD mouse models, the BDNFmet/leu mice showed reduced dendritic arborization, altered spines, and impaired synaptic transmission and plasticity in the hippocampus. They also exhibited ASD-like phenotypes, including stereotypical behaviors and deficits in social interaction. Moreover, the plasma proBDNF/mBDNF ratio was significantly increased in ASD patients compared to normal children in a case-control study. Thus, deficits in proBDNF to mBDNF conversion in the brain may contribute to ASD-like behaviors, and plasma proBDNF/mBDNF ratio may be a potential biomarker for ASD.

Autism patient-derived SHANK2BY29X mutation affects the development of ALDH1A1 negative dopamine neuron.

Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental conditions. Different mutations on a single ASD gene contribute to heterogeneity of disease phenotypes, possibly due to functional diversity of generated isoforms. SHANK2, a causative gene in ASD, demonstrates this phenomenon, but there is a scarcity of tools for studying endogenous SHANK2 proteins in an isoform-specific manner. Here, we report a point mutation on SHANK2, which is found in a patient with autism, located on exon of the SHANK2B transcript variant (NM_133266.5), hereby SHANK2BY29X. This mutation results in an early stop codon and an aberrant splicing event that impacts SHANK2 transcript variants distinctly. Induced pluripotent stem cells (iPSCs) carrying this mutation, from the patient or isogenic editing, fail to differentiate into functional dopamine (DA) neurons, which can be rescued by genetic correction. Available SMART-Seq single-cell data from human midbrain reveals the abundance of SHANK2B transcript in the ALDH1A1 negative DA neurons. We then show that SHANK2BY29X mutation primarily affects SHANK2B expression and ALDH1A1 negative DA neurons in vitro during early neuronal developmental stage. Mice knocked in with the identical mutation exhibit autistic-like behavior, decreased occupancy of ALDH1A1 negative DA neurons and decreased dopamine release in ventral tegmental area (VTA). Our study provides novel insights on a SHANK2 mutation derived from autism patient and highlights SHANK2B significance in ALDH1A1 negative DA neuron.

CCDC66 mutations are associated with high myopia through affected cell mitosis.

BACKGROUND: High myopia (HM) refers to an eye refractive error exceeding -5.00 D, significantly elevating blindness risk. The underlying mechanism of HM remains elusive. Given the extensive genetic heterogeneity and vast genetic base opacity, it is imperative to identify more causative genes and explore their pathogenic roles in HM. METHODS: We employed exome sequencing to pinpoint the causal gene in an HM family. Sanger sequencing was used to confirm and analyse the gene mutations in this family and 200 sporadic HM cases. Single-cell RNA sequencing was conducted to evaluate the gene's expression patterns in developing human and mouse retinas. The CRISPR/Cas9 system facilitated the gene knockout cells, aiding in the exploration of the gene's function and its mutations. Immunofluorescent staining and immunoblot techniques were applied to monitor the functional shifts of the gene mutations at the cellular level. RESULTS: A suspected nonsense mutation (c.C172T, p.Q58X) in CCDC66 was found to be co-segregated with the HM phenotype in the family. Additionally, six other rare variants were identified among the 200 sporadic patients. CCDC66 was consistently expressed in the embryonic retinas of both humans and mice. Notably, in CCDC66-deficient HEK293 cells, there was a decline in cell proliferation, microtube polymerisation rate and ace-tubulin level. Furthermore, the mutated CCDC66 failed to synchronise with the tubulin system during Hela cell mitosis, unlike its wild type counterpart. CONCLUSIONS: Our research indicates that the CCDC66 variant c.C172T is associated with HM. A deficiency in CCDC66 might disrupt cell proliferation by influencing the mitotic process during retinal growth, leading to HM.

Genetic landscape of human mitochondrial genome using whole-genome sequencing.

Increasing evidences suggest that mitochondrial dysfunction is implicated in diseases and aging, and whole-genome sequencing (WGS) is the most unbiased method in analyzing the mitochondrial genome (mtDNA). However, the genetic landscape of mtDNA in the Chinese population has not been fully examined. Here, we described the genetic landscape of mtDNA using WGS data from Chinese individuals (n = 3241). We identified 3892 mtDNA variants, of which 3349 (86%) were rare variants. Interestingly, we observed a trend toward extreme heterogeneity of mtDNA variants. Our study observed a distinct purifying selection on mtDNA, which inhibits the accumulation of harmful heteroplasmies at the individual level: (1) mitochondrial dN/dS ratios were much <1; (2) the dN/dS ratio of heteroplasmies was higher than homoplasmies; (3) heteroplasmies had more indels and predicted deleterious variants than homoplasmies. Furthermore, we found that haplogroup M (20.27%) and D (20.15%) had the highest frequencies in the Chinese population, followed by B (18.51%) and F (16.45%). The number of variants per individual differed across haplogroup groups, with a higher number of homoplasmies for the M lineage. Meanwhile, mtDNA copy number was negatively correlated with age but positively correlated with the female sex. Finally, we developed an mtDNA variation database of Chinese populations called MTCards (http://genemed.tech/mtcards/) to facilitate the query of mtDNA variants in this study. In summary, these findings contribute to different aspects of understanding mtDNA, providing a better understanding of the genetic basis of mitochondrial-related diseases.

Omentin-1 inhibits the development of benign prostatic hyperplasia by attenuating local inflammation.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a prevalent disease affecting elderly men, with chronic inflammation being a critical factor in its development. Omentin-1, also known as intelectin-1 (ITLN-1), is an anti-inflammatory protein primarily found in the epithelial cells of the small intestine. This study aimed to investigate the potential of ITLN-1 in mitigating BPH by modulating local inflammation in the prostate gland. METHODS: Our investigation involved two in vivo experimental models. Firstly, ITLN-1 knockout mice (Itln-1-/-) were used to study the absence of ITLN-1 in BPH development. Secondly, a testosterone propionate (TP)-induced BPH mouse model was treated with an ITLN-1 overexpressing adenovirus. We assessed BPH severity using prostate weight index and histological analysis, including H&E staining, immunohistochemistry, and enzyme-linked immunosorbent assay. In vitro, the impact of ITLN-1 on BPH-1 cell proliferation and inflammatory response was evaluated using cell proliferation assays and enzyme-linked immunosorbent assay. RESULTS: In vivo, Itln-1-/- mice exhibited elevated prostate weight index, enlarged lumen area, and higher TNF-α levels compared to wild-type littermates. In contrast, ITLN-1 overexpression in TP-induced BPH mice resulted in reduced prostate weight index, lumen area, and TNF-α levels. In vitro studies indicated that ITLN-1 suppressed the proliferation of prostate epithelial cells and reduced TNF-α production in macrophages, suggesting a mechanism involving the inhibition of macrophage-mediated inflammation. CONCLUSION: The study demonstrates that ITLN-1 plays a significant role in inhibiting the development of BPH by reducing local inflammation in the prostate gland. These findings highlight the potential of ITLN-1 as a therapeutic target in the management of BPH.

Efficacy of Recombinant Human Parathyroid Hormone 1-34 and Vitamin K2 Combination Therapy in Postmenopausal Osteoporosis.

This study aimed to assess the efficacy and safety of a combined recombinant human parathyroid hormone 1-34 [rhPTH (1-34)] and vitamin K2 therapy versus vitamin K2 alone in the treatment of postmenopausal osteoporosis. A total of 77 postmenopausal osteoporosis patients were randomly divided into two groups. Patients in one group received vitamin K2 alone, while patients in the other group received a combination of rhPTH (1-34) and vitamin K2. Bone mineral density (BMD), electrolyte levels, pain scores, bone metabolism levels, and adverse drug reactions were compared pre- and post-treatment. Both two treatments improved BMD, blood calcium concentrations, pain scores, and increased osteocalcin and osteoprotegerin levels. Notably, the combined rhPTH (1-34) and vitamin K2 treatment demonstrated superior efficacy in improving BMD and bone metabolism markers. Furthermore, there was no significant difference in the incidence of adverse reactions between the two groups, indicating the safety of the combined treatment. In summary, the combined therapy of rhPTH (1-34) and vitamin K2 exhibited more potent efficacy in the treatment of postmenopausal osteoporosis, more effectively enhancing BMD and bone metabolism markers than vitamin K2 alone, without a significant increase in adverse reactions.

Synthesis of α/ß-Aromatic Peroxy Thiols Mediated by Iodine Source.

Peroxygenated compounds have wide applications in various fields, including chemistry, pharmaceutical chemistry, medicine, and materials science. However, there is still a need for more efficient and environmentally friendly synthesis methods for such compounds. Herein, we investigated the two-step, one-pot, regioselective synthesis of α/ß-aromatic peroxy thiols. We explored various substrates and solvents for the reaction and identified the optimal reaction conditions. We successfully obtained several peroxy thiols in moderate to good yields via the selective generation of effective intermediates of iodoalkyl peroxides at room temperature without the need for metal catalysts.

Transition metal-free C(sp3)-H selenation of ß-ketosulfones.

The installation of selenium groups has become an essential step across a number of industries such as agrochemicals, drug discovery, and materials. However, direct C(sp3)-H selenation, which is most atom economical, remains a formidable challenge, and only a few examples have been reported to date. In this article, we introduce the transition metal-free C(sp3)-H selenation with the easily available ß-ketosulfones and diselenides as the material source. This benign protocol permits access to a broad spectrum of α-aryl(alkyl) seleno-ß-ketosulfones in high yields with outstanding functional group compatibility. Distinct advantages of this protocol over all previous methods encompass the utilization of base and air as an oxidant, room temperature, and enhanced green chemistry matrices.

Progressive gray matter atrophy in parkinsonian variant of multiple system atrophy assessed by using causal structural covariance network.

INTRODUCTION: Multiple system atrophy (MSA), a rare neurodegenerative disease, is usually accompanied by brain morphological alterations. However, the causal relationships between progressive gray matter atrophy in MSA parkinsonian (MSA-P) subtype remain unknown. METHODS: In total, thirty-five MSA-P patients and thirty-five healthy controls (HC) underwent three-dimensional high-resolution T1-weighted structural imaging and voxel-based morphometry analysis. The causal structural covariance network (CaSCN) of gray matter was assessed to explore the causal relationships in MSA-P. RESULTS: With greater illness duration, the reduction of gray matter was originated from right cerebellum and progressed to bilateral cerebellum, fusiform gyrus, insula, putamen, caudate nucleus, frontal lobe, right angular gyrus, right precuneus, left middle occipital lobe and left inferior temporal lobe, then expanded to midbrain, bilateral para-hippocampus, thalamus, temporal lobe, inferior parietal lobule (IPL), precentral gyrus, postcentral gyrus and middle cingulate cortex. The right cerebellum was revealed to be the core node of the directional network and projected positive causal effects to bilateral cerebellum, caudate nucleus and left IPL. CONCLUSION: MSA-P patients showed progression of gray matter atrophy over time, with the right cerebellum probably as a primary hub. Furthermore, the early structural vulnerability of cerebellum in MSA-P may play a pivotal role in the modulation of motor and non-motor circuits at the structural level.

GLRA2 gene mutations cause high myopia in humans and mice.

BACKGROUND: High myopia (HM) is a leading cause of blindness that has a strong genetic predisposition. However, its genetic and pathogenic mechanisms remain largely unknown. Thus, this study aims to determine the genetic profile of individuals from two large Chinese families with HM and 200 patients with familial/sporadic HM. We also explored the pathogenic mechanism of HM using HEK293 cells and a mouse model. METHODS: The participants underwent genome-wide linkage analysis and exome sequencing. Visual acuity, electroretinogram response, refractive error, optical parameters and retinal rod cell genesis were measured in knockout mice. Immunofluorescent staining, biotin-labelled membrane protein isolation and electrophysiological characterisation were conducted in cells transfected with overexpression plasmids. RESULTS: A novel HM locus on Xp22.2-p11.4 was identified. Variant c.539C>T (p.Pro180Leu) in GLRA2 gene was co-segregated with HM in the two families. Another variant, c.458G>A (p.Arg153Gln), was identified in a sporadic sample. The Glra2 knockout mice showed myopia-related phenotypes, decreased electroretinogram responses and impaired retinal rod cell genesis. Variants c.458G>A and c.539C>T altered the localisation of GlyRα2 on the cell membrane and decreased agonist sensitivity. CONCLUSION: GLRA2 was identified as a novel HM-causing gene. Its variants would cause HM through altered visual experience by impairing photoperception and visual transmission.

Performance evaluation of differential splicing analysis methods and splicing analytics platform construction.

A proportion of previously defined benign variants or variants of uncertain significance in humans, which are challenging to identify, may induce an abnormal splicing process. An increasing number of methods have been developed to predict splicing variants, but their performance has not been completely evaluated using independent benchmarks. Here, we manually sourced ∼50 000 positive/negative splicing variants from > 8000 studies and selected the independent splicing variants to evaluate the performance of prediction methods. These methods showed different performances in recognizing splicing variants in donor and acceptor regions, reminiscent of different weight coefficient applications to predict novel splicing variants. Of these methods, 66.67% exhibited higher specificities than sensitivities, suggesting that more moderate cut-off values are necessary to distinguish splicing variants. Moreover, the high correlation and consistent prediction ratio validated the feasibility of integration of the splicing prediction method in identifying splicing variants. We developed a splicing analytics platform called SPCards, which curates splicing variants from publications and predicts splicing scores of variants in genomes. SPCards also offers variant-level and gene-level annotation information, including allele frequency, non-synonymous prediction and comprehensive functional information. SPCards is suitable for high-throughput genetic identification of splicing variants, particularly those located in non-canonical splicing regions.

Optoelectronic Torque Measurement System Based on SAPSO-RBF Algorithm.

The torque is a significant indicator reflecting the comprehensive operational characteristics of a power system. Thus, accurate torque measurement plays a pivotal role in ensuring the safety and stability of the system. However, conventional torque measurement systems predominantly rely on strain gauges adhered to the shaft, often leading to reduced accuracy, poor repeatability, and non-traceability due to the influence of strain gauge adhesion. To tackle the challenge, this paper introduces a photoelectric torque measurement system. Quadrants of photoelectric sensors are employed to capture minute deformations induced by torque on the rotational axis, converting them into measurable voltage. Subsequently, the system employs the radial basis function neural network optimized by simulated annealing combined with particle swarm algorithm (SAPSO-RBF) to establish a correlation between measured torque values and standard references, thereby calibrating the measured values. Experimental results affirm the system's capability to accurately determine torque measurements and execute calibration, minimizing measurement errors to 0.92%.

The autism risk gene CNTN4 modulates dendritic spine formation.

Contactin 4 (CNTN4) is a crucial synaptic adhesion protein that belongs to the contactin superfamily. Evidence from both human genetics and mouse models suggests that synapse formation and structural deficits strongly correlate with neurodevelopmental disorders, including autism. In addition, several lines of evidence suggest that CNTN4 is associated with the risk of autism. However, the biological functions of CNTN4 in neural development and disease pathogenesis are poorly understood. In this study, we investigated whether and how CNTN4 is autonomously involved in the development of dendrites and dendritic spines in cortical neurons. Disruption of Cntn4 decreased the number of excitatory synapses, which led to a reduction in neural activity. Truncated proteins lacking the signal peptide, FnIII domains or GPI domain lacked the ability to regulate dendritic spine formation, indicating that CNTN4 regulates dendritic spine density through a mechanism dependent on FnIII domains. Importantly, we revealed that autism-related variants lacked the ability to regulate spine density and neural activity. In conclusion, our study suggests that CNTN4 is essential for promoting dendrite growth and dendritic spine formation and that disruptive variants of CNTN4 interfere with abnormal synapse formation and may increase the risk of autism.

The tumour-associated stroma correlates with poor clinical outcomes and immunoevasive contexture in patients with upper tract urothelial carcinoma: results from a multicenter real-world study (TSU-01 Study).

BACKGROUND: In this real-world study, we aimed to elucidate the predictive value of tumour-associated stroma for clinical prognostic and therapeutic response in upper tract urothelial carcinoma (UTUC) by reviewing the clinicopathologic characteristics of 1015 UTUC patients through a nationwide multicenter analysis. METHODS: The tumour-stroma ratio (TSR) was assessed based on tissue sections stained for hematoxylin and eosin (H&E), and patients were further stratified into stroma-high (>50% stroma) and stroma-low group (≤50% stroma). Kaplan-Meier curve and Cox regression hazard analysis were conducted to assess the survival outcomes of UTUC patients. Bioinformatics analysis and immunostaining analysis were applied to portray the tumour microenvironment (TME). RESULTS: Stroma-high UTUC was significantly associated with poorer survival outcomes and inferior chemotherapeutic responsiveness. Our established nomogram achieved a high prognostic accuracy in predicting overall survival and cancer-specific survival in both of the discovery cohort (area under the curve [AUC] 0.663 and 0.712) and the validation cohort (AUC 0.741 and 0.747). Moreover, stroma-high UTUC was correlated with immunoevasive TME accompanied by increased cancer-associated fibroblasts, tumour-associated macrophages and, conspicuously a cluster of highly exhausted CD8+ T cells. CONCLUSION: Our results showed stroma-high UTUC was associated with an inferior prognosis and an immunoevasive TME with exhausted CD8+ T cells in UTUC patients. Our TSR-based nomogram could be used to refine prognosis and inform treatment decisions of patients with UTUC.

GSN gene frameshift mutations in Alzheimer's disease.

BACKGROUND: The pathogenic missense mutations of the gelsolin (GSN) gene lead to familial amyloidosis of the Finnish type (FAF); however, our previous study identified GSN frameshift mutations existed in patients with Alzheimer's disease (AD). The GSN genotype-phenotype heterogeneity and the role of GSN frameshift mutations in patients with AD are unclear. METHOD: In total, 1192 patients with AD and 1403 controls were screened through whole genome sequencing, and 884 patients with AD were enrolled for validation. Effects of GSN mutations were evaluated in vitro. GSN, Aß42, Aß40 and Aß42/40 were detected in both plasma and cerebrospinal fluid (CSF). RESULTS: Six patients with AD with GSN P3fs and K346fs mutations (0.50%, 6/1192) were identified, who were diagnosed with AD but not FAF. In addition, 13 patients with AD with GSN frameshift mutations were found in the validation cohort (1.47%, 13/884). Further in vitro experiments showed that both K346fs and P3fs mutations led to the GSN loss of function in inhibiting Aß-induced toxicity. Moreover, a higher level of plasma (p=0.001) and CSF (p=0.005) GSN was observed in AD cases than controls, and a positive correlation was found between the CSF GSN and CSF Aß42 (r=0.289, p=0.009). Besides, the GSN level was initially increasing and then decreasing with the disease course and cognitive decline. CONCLUSIONS: GSN frameshift mutations may be associated with AD. An increase in plasma GSN is probably a compensatory reaction in AD, which is a potential biomarker for early AD.

Comparison of minimally invasive versus open pelvic organ-preserving radical cystectomy in female patients with bladder cancer: a multicenter propensity score matching analysis.

PURPOSE: To compare the perioperative and oncologic outcomes between minimally invasive pelvic organ-preserving radical cystectomy (MIPOPRC) and open pelvic organ-preserving radical cystectomy (open POPRC) among female patients with bladder cancer (BCa). METHODS: We identified female patients who underwent POPRC for BCa at three centers between January 2006 and April 2018. Female patients who underwent open POPRC were matched with those who underwent MIPOPRC using 1:1 propensity score (PS) matching. The patient demographics and perioperative and oncologic outcomes were evaluated for the comparison between MIPOPRC and open POPRC. RESULTS: Among the 158 patients enrolled, 83 patients underwent MIPOPRC, and 75 underwent open POPRC. A total of 60 MIPOPRC and 60 open POPRC patients were matched successfully. The cancer-specific survival (CSS) and recurrence-free survival (RFS) did not differ significantly in the propensity score-weighted cohort (p = 0.297 and p = 0.600, respectively). Subgroup analysis by age and pathologic stage in the matched cohort revealed that CSS and RFS were with no differences among all subgroups. Moreover, multivariable Cox regression analyses showed that the surgical approach (MIPOPRC vs open POPRC) was not a predictor of CSS (p = 0.250). CONCLUSION: MIPOPRC was non-inferior to open POPRC in terms of oncologic outcomes among female patients. MIPOPRC could be technically feasible in selected female patients with BCa.

Association between history of miscarriage and autism spectrum disorder.

This case-control study was designed to examine the association between different types of miscarriage history and autism spectrum disorder (ASD), and determine whether the number of miscarriage history affects the risk of ASD. All of 2274 children with ASD and 1086 healthy controls were recruited. Sociodemographic and prenatal, perinatal, and neonatal characteristics were compared between the two groups. Multivariable logistic regression analyses were applied to investigate association between miscarriage history and ASD. Stratified analyses based on sex and types of miscarriages were similarly performed. History of miscarriage was potential risk factors for ASD ([aOR] = 2.919; 95% [CI] = 2.327-3.517). Stratified analyses revealed that induced ([aOR] = 2.763, 95% [CI] = 2.259-3.379) and spontaneous miscarriage history ([aOR] = 3.341, 95% [CI] = 1.939-4.820) were associated with high risk of ASD, respectively. A sex-biased ratio in the risk of ASD was observed between females ([aOR] = 3.049, 95% [CI] = 2.153-4.137) and males ([aOR] = 2.538, 95% [CI] = 1.978-3.251). Stratified analysis of induced miscarriage history revealed that only iatrogenic miscarriage history was associated with an increased risk ASD ([aOR] = 2.843, 95% [CI] = 1.534-4.268). Also, multiple spontaneous miscarriage histories ([aOR] = 1.836, 95% [CI] = 1.252-2.693) were associated with higher autism risk than one spontaneous miscarriages history ([aOR] = 3.016, 95% [CI] = 1.894-4.174). In conclusion, miscarriage history is related to an increased risk for ASD in offspring, which is affected by the types of miscarriage and sex of the fetus.