Gut microbiota and autism spectrum disorders: a bidirectional Mendelian randomization study.

Background: In recent years, observational studies have provided evidence supporting a potential association between autism spectrum disorder (ASD) and gut microbiota. However, the causal effect of gut microbiota on ASD remains unknown. Methods: We identified the summary statistics of 206 gut microbiota from the MiBioGen study, and ASD data were obtained from the latest Psychiatric Genomics Consortium Genome-Wide Association Study (GWAS). We then performed Mendelian randomization (MR) to determine a causal relationship between the gut microbiota and ASD using the inverse variance weighted (IVW) method, simple mode, MR-Egger, weighted median, and weighted model. Furthermore, we used Cochran's Q test, MR-Egger intercept test, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and leave-one-out analysis to identify heterogeneity and pleiotropy. Moreover, the Benjamin-Hochberg approach (FDR) was employed to assess the strength of the connection between exposure and outcome. We performed reverse MR analysis on the gut microbiota that were found to be causally associated with ASD in the forward MR analysis to examine the causal relationships. The enrichment analyses were used to analyze the biological function at last. Results: Based on the results of IVW results, genetically predicted family Prevotellaceae and genus Turicibacter had a possible positive association with ASD (IVW OR=1.14, 95% CI: 1.00-1.29, P=3.7×10-2), four gut microbiota with a potential protective effect on ASD: genus Dorea (OR=0.81, 95% CI: 0.69-0.96, P=1.4×10-2), genus Ruminiclostridium5 (OR=0.81, 95% CI: 0.69-0.96, P=1.5×10-2), genus Ruminococcus1 (OR=0.83, 95% CI: 0.70-0.98, P=2.8×10-2), and genus Sutterella (OR=0.82, 95% CI: 0.68-0.99, P=3.6×10-2). After FDR multiple-testing correction we further observed that there were two gut microbiota still have significant relationship with ASD: family Prevotellaceae (IVW OR=1.24; 95% CI: 1.09-1.40, P=9.2×10-4) was strongly positively correlated with ASD and genus RuminococcaceaeUCG005 (IVW OR=0.78, 95% CI: 0.67-0.89, P=6.9×10-4) was strongly negatively correlated with ASD. The sensitivity analysis excluded the influence of heterogeneity and horizontal pleiotropy. Conclusion: Our findings reveal a causal association between several gut microbiomes and ASD. These results deepen our comprehension of the role of gut microbiota in ASD's pathology, providing the foothold for novel ideas and theoretical frameworks to prevent and treat this patient population in the future.

A novel homozygous HES7 splicing variant causing spondylocostal dysostosis 4: a case report.

Background: Spondylocostal dysostosis 4 (SCDO4) is characterized by short stature (mainly short trunk), dyspnea, brain meningocele, and spina bifida occulta, which is caused by homozygous or compound heterozygous HES7 (HES family bHLH transcription factor 7) variants. The incidence of SCDO4 remains unknown due to the extremely low number of cases. This study reveals a novel homozygous HES7 splicing variant causing SCDO4 and reviews all the previously reported HES7 variants and corresponding symptoms, providing a comprehensive overview of the phenotypes and genotypes of HES7 variants. Case presentation: This case report focuses on a Chinese neonate who was first hospitalized for tachypnea, cleft palate, and short trunk. After a series of auxiliary examinations, the patient was also found to have deformities of vertebrae and rib, left hydronephrosis, and patent foramen ovale. He underwent surgery for congenital hydronephrosis at 5 months old and underwent cleft palate repair when he was 1 year old. After two and half years of follow-up, the boy developed normally. A novel homozygous HES7 splicing variant (c.226+1G>A, NM_001165967.2) was identified in the proband by whole-exome sequencing and verified by Sanger sequencing. The variant was inherited from both parents and minigene assays demonstrated that this variant resulted in the retention of intron3 in the HES7 transcript. Including this case, a total of six HES7 variants and 13 patients with SCDO4 have been reported. Conclusions: Our findings expand the genotype-phenotype knowledge of SCDO4 and provide new evidence for genetic counseling.

Identification of rare variants causing urea cycle disorders: A clinical, genetic, and biophysical study.

Urea cycle disorders (UCDs) are a group of rare metabolic conditions characterized by hyperammonemia and a broad spectrum of phenotypic severity. They are caused by the congenital deficiency in the eight biomolecules involved in urea cycle. In the present study, five cases of UCD were recruited and submitted to a series of clinical, biochemical, and genetic analysis with a combination of high throughput techniques. Moreover, in silico analysis was conducted on the identified missense genetic variants. Various clinical and biochemical indications (including profiles of amino acids and urinary orotic acids) of UCD were manifested by the five probands. Sequence analysis revealed nine diagnostic variants, including three novel ones, which caused Argininosuccinic aciduria (ASA) in one case, Carbamoyl phosphate synthetase 1deficiency (CPS1D) in two cases, Ornithine transcarbamylase deficiency (OTCD) in one case, and Citrin deficiency in 1case. Results of in silico biophysical analysis strongly suggested the pathogenicity of each the five missense variants and provided insight into their intramolecular impacts. In conclusion, this study expanded the genetic variation spectrum of UCD, gave solid evidence for counselling to the affected families, and should facilitate the functional study on the proteins in urea cycle.

Relationship between serum IL-1ß and insomnia and liver depression in patients with perimenopausal non-organic sleep disorder.

The aim of the study was to detect the expression of interleukin-1ß (IL-1ß) in serum of patients with perimenopausal non-organic sleep disorder (PNSD) and to study the relationship between IL-1ß and the severity of insomnia and liver depression, so as to benefit the prevention of PNSD. A total of 268 cases of perimenopausal patients from the Department of Traditional Chinese Medicine of Fujian Provincial Hospital and the Department of Traditional Chinese Medicine of Jinshan Branch of Fujian Provincial Hospital were selected from March 2014 to June 2017. Among them, 182 patients developed non-organic insomnia (observation group). The remaining 86 patients were included in the control group. Serum levels of IL-1ß were measured by enzyme-linked immunosorbent assay (ELISA). Scores of liver depression were determined and graded. Pittsburgh Sleep Quality Index (PSQI) was used to assess the severity of insomnia. Spearman's correlation analysis was used to analyze the correlation between PSQI, IL-1ß and liver depression grade. Scores of liver depression in the observation group were significantly higher than those in control group (p<0.05). In the observation group, and PSQI scores in patients with different grades of liver depression are significantly different (p<0.05). Average level of IL-1ß in the observation group was significantly higher than that in control group (p<0.05). With the increase of liver depression grade, the expression level of IL-1ß was also increased (p<0.05). Spearman's correlation analysis showed that PSQI was positively correlated with liver depression score, and the level of IL-1ß was positively correlated with the liver depression grade in patients with PNSD. (r=0.724, p=0.012; r=0.765, p=0.008). Expression of IL-1ß in women with PNSD is significantly upregulated, and different degrees of liver depression also exist. Higher expression level of IL-1ß is accompanied by more serious liver depression and higher degree of insomnia.