The Association Between STAT4 rs7574865 Polymorphism and the Susceptibility of Autoimmune Thyroid Disease: A Meta-Analysis

Objectives: The signal transducer and activator of transcription 4 (STAT4) gene encodes an important transcription factor that transmits signals induced by several cytokines associated with autoimmune diseases and has been identified as a susceptibility gene for numerous autoimmune disorders. The association between STAT4 rs7574865 polymorphism and the susceptibility of autoimmune thyroid disease (AITD) has been investigated in previous case-control studies. However, the investigation results were inconsistent. Hence, a meta-analysis was performed to draw a more reliable conclusion about it.Methods: All relevant studies were searched in Embase, PubMed, Web of Science, and China National Knowledge Infrastructure, till August 20, 2018. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the association.Results: A total of five independent case-control studies with 1707 AITD patients and 2316 controls were included in the present meta-analysis. The overall pooled analysis indicated that STAT4 rs7574865 polymorphism was significantly associated with AITD susceptibility [TT vs. GG: OR = 1.63, 95%CI = 1.24–2.15, PZ = 0.0005; TT vs. (TG+GG): OR = 1.55, 95%CI = 1.26–1.91, PZ < 0.0001]. However, the subgroup analysis showed a significant association of STAT4 rs7574865 polymorphism with AITD susceptibility in Asian population, but not in African population. STAT4 rs7574865 polymorphism was significantly associated both with Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) susceptibility.Conclusion: This meta-analysis showed a significant association between STAT4 rs7574865 polymorphism and AITD susceptibility. However, further studies with larger sample sizes and other ethnicities are still required to confirm the findings

De novo mutations in ARID1B associated with both syndromic and non-syndromic short stature

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Rare Copy Number Variations in a Chinese Cohort of Autism Spectrum Disorder

Autism spectrum disorder (ASD) is heterogeneous in symptom and etiology. Rare copy number variations (CNVs) are important genetic factors contributing to ASD. Currently chromosomal microarray (CMA) detecting CNVs is recommended as a first-tier diagnostic assay, largely based on research in North America and Europe. The feature of rare CNVs has not been well characterized in ASD cohorts from non-European ancestry. In this study, high resolution CMA was utilized to investigate rare CNVs in a Chinese cohort of ASD (n = 401, including 177 mildly/moderately and 224 severely affected individuals), together with an ancestry-matched control cohort (n = 197). Diagnostic yield was about 4.2%, with 17 clinically significant CNVs identified in ASD individuals, of which 12 CNVs overlapped with recurrent autism risk loci or genes. Autosomal rare CNV burden analysis showed an overrepresentation of rare loss events in ASD cohort, whereas the rate of rare gain events correlated with the phenotypic severity. Further analysis showed rare losses disrupting genes highly intolerant of loss-of-function variants were enriched in the ASD cohort. Among these highly constrained genes disrupted by rare losses, RIMS2 is a promising candidate contributing to ASD risk. This pilot study evaluated clinical utility of CMA and the feature of rare CNVs in Chinese ASD, with candidate genes identified as potential risk factors

Genetic Diagnostic Evaluation of Trio-Based Whole Exome Sequencing Among Children With Diagnosed or Suspected Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a group of clinically and genetically heterogeneous neurodevelopmental disorders. Recent tremendous advances in the whole exome sequencing (WES) enable rapid identification of variants associated with ASD including single nucleotide variations (SNVs) and indels. To further explore genetic etiology of ASD in Chinese children with negative findings of copy number variants (CNVs), we applied WES in 80 simplex families with a single affected offspring with ASD or suspected ASD, and validated variations predicted to be damaging by Sanger sequencing. The results showed that an overall diagnostic yield of 8.8% (9.2% in the group of ASD and 6.7% in the group of suspected ASD) was observed in our cohort. Among patients with diagnosed ASD, developmental delay or intellectual disability (DD/ID) was the most common comorbidity with a diagnostic yield of 13.3%, followed by seizures (50.0%) and craniofacial anomalies (40.0%). All of identified de novo SNVs and indels among patients with ASD were loss of function (LOF) variations and were slightly more frequent among female (male vs. female: 7.3% vs. 8.5%). A total of seven presumed causative genes (CHD8, AFF2, ADNP, POGZ, SHANK3, IL1RAPL1, and PTEN) were identified in this study. In conclusion, WES is an efficient diagnostic tool for diagnosed ASD especially those with negative findings of CNVs and other neurological disorders in clinical practice, enabling early identification of disease related genes and contributing to precision and personalized medicine

Genetic Evaluation of 114 Chinese Short Stature Children in the Next Generation Era: a Single Center Study

Background/Aims: The genetics of human height is a frequently studied and complex issue. However, there is limited genetic research of short stature. To uncover the subgroup of patients to have higher yield and to propose a simplified diagnostic algorithm in the next generation era. Methods: This study included 114 Chinese children with height SDS ≤ -2.5 and unknown etiology from 2014 to 2015. Target/whole exome sequencing (referred as NGS) and chromosomal microarray analysis (CMA) were performed on the enrolled patients sequentially to identify potential genetic etiologies. The samples solved by NGS and CMA were retrospectively studied to evaluate the clinical pathway of the patients following a standard diagnostic algorithm. Results: In total, a potential genetic etiology was identified in 41 (36%) patients: 38 by NGS (33.3%), two by CMA (1.8%), and an additional one by both (0.9%). There were 46 different variants in 29 genes and 2 pathogenic CNVs identified. The diagnostic yield was significantly higher in patients with facial dysmorphism or skeletal abnormalities than those without the corresponding phenotype (P=0.006 and P=0.009, respectively, Pearson’s χ2 test). Retrospectively study the cohort indicate 83.3% patients eventually would be evaluated by NGS/CMA. Conclusion: This study confirms the utility of high-throughput molecular detection techniques for the etiological diagnosis of undiagnosed short stature and suggests that NGS could be used as a primary diagnostic strategy. Patients with facial dysmorphism and/or skeletal abnormalities are more likely to have a known genetic etiology. Moving NGS forward would simplified the diagnostic algorithm

MiR-218 Inhibits Invasion and Metastasis of Gastric Cancer by Targeting the Robo1 Receptor

MicroRNAs play key roles in tumor metastasis. Here, we describe the regulation and function of miR-218 in gastric cancer (GC) metastasis. miR-218 expression is decreased along with the expression of one of its host genes, Slit3 in metastatic GC. However, Robo1, one of several Slit receptors, is negatively regulated by miR-218, thus establishing a negative feedback loop. Decreased miR-218 levels eliminate Robo1 repression, which activates the Slit-Robo1 pathway through the interaction between Robo1 and Slit2, thus triggering tumor metastasis. The restoration of miR-218 suppresses Robo1 expression and inhibits tumor cell invasion and metastasis in vitro and in vivo. Taken together, our results describe a Slit-miR-218-Robo1 regulatory circuit whose disruption may contribute to GC metastasis. Targeting miR-218 may provide a strategy for blocking tumor metastasis