Three Novel ARID1B Variations in Coffin-Siris Syndrome Patients.

Coffin-Siris syndrome (CSS) (OMIM #135900) involves multiple congenital malformations, including hypotonia, short stature, sparse scalp hair, a coarse face, prominent eyebrows, a wide mouth, delayed bone age, and hypoplastic or absent fifth fingers/toes or nails, together with developmental delay. The cause of CSS is suggested to be related to alterations in the BRG- or HRBM-associated factor (BAF) pathway in humans. In this gene family, pathogenic variations in the AT-rich interactive domain-containing protein 1B (ARID1B) gene are revealed to be a significant element causing neurodevelopmental disability in patients with CSS. Herein, we describe the clinical features and gene variations in four Chinese patients with CSS. All the patients shared common features of short fifth fingers/toes or hypoplastic nails, coarse facial features, thick eyebrows, long cilia, a flat nasal bridge, a broad nose, a wide mouth, a high palate, and hypotonia. Besides, they had an intellectual disability, language, and motor developmental delay. Candidate genes were screened for variations using polymerase chain reaction (PCR) and sequencing. The variations were sequenced by next-generation sequencing and confirmed by first-generation sequencing. Exome sequencing suggested four de novo variations in the ARID1B gene in four unrelated patients. These included two frameshift variations (c.3581delC, c.6661_6662insG) and two nonsense variations (c.1936C>T, c.2248C>T). Of the four variations, three variations were novel. The results in our present study broaden the understanding of the disease and further interpret the molecular genetic mechanism of these rare variations in CSS.

Elevated expression of microRNA-378 in children with asthma aggravates airway remodeling by promoting the proliferation and apoptosis resistance of airway smooth muscle cells.

The present study determined the expression of microRNA (miR)-378 in the peripheral blood and lung tissues of children with asthma, and investigated its effect and mechanism of action on the biological functions of airway smooth muscle cells. A total of 23 asthmatic children and 15 healthy children were included in the study. Peripheral blood and tissues were obtained from asthmatic children. Healthy children provided peripheral blood. Quantitative real-time polymerase chain reaction was used to determine the expression of miR-378. Airway smooth muscle cells were isolated and cultured in vitro. The cells were transfected with miR-378 mimics or miR-378 inhibitor. Following transfection, proliferation of the cells was determined using the CCK-8 assay. In addition, flow cytometry was used to detect the cell cycles and apoptosis of smooth muscle cells. Western blotting was performed to determine the expression of extracellular matrix proteins in smooth muscle cells. Furthermore, bioinformatics was used to predict potential target genes of miR-378 and their downstream signaling pathways. Results indicated that the expression of miR-378 in peripheral blood and lung tissues from asthmatic children was increased compared with that in healthy children. Serum from asthmatic children promoted the proliferation of smooth muscle cells in vitro by affecting the cell cycle, and enhanced apoptotic resistance of smooth muscle cells. Notably, overexpression of miR-378 increased the proliferation of smooth muscle cells by affecting the cell cycle, and this upregulated apoptotic resistance of smooth muscle cells and enhanced the expression of extracellular matrix-related proteins in smooth muscle cells. However, downregulation of miR-378 expression reversed the promoting effect of serum from asthmatic children on the biological functions of smooth muscle cells. These findings suggested that miR-378 possibly affects the proliferation, apoptosis and motility of airway smooth muscle cells via downstream signaling pathways. To conclude, the present study demonstrated that miR-378 expression was elevated in the peripheral blood and lung tissues from children with asthma. Furthermore, miR-378 promoted the biological functions of extracellular matrix-related proteins of smooth muscle cells, and possibly exerts its effect via its target genes through downstream signaling pathways.

Polymorphism of OAS2 rs739901 C/A Involves the Susceptibility to EV71 Infection in Chinese Children.

This study aimed to assess the relationship of OAS2 rs739901 5,-flanking C/A polymorphisms with the susceptibility to Enterovirus-71 (EV71) infection. We investigated 294 hand-foot-mouth disease (HFMD) Chinese children with EV71 infection (165 mild cases and 129 encephalitis cases). The improved multiplex ligation detection reaction (iMLDR) technique was used to test the genotypes. In EV71-infected patients, the CA genotype distribution (P=0.007), A allele frequency (OR 1.32,95% CI 1.0-1.7, P=0.034) and CA+AA carriage frequency (P=0.003) of OAS2 rs739901 5'-flanking were obviously elevated as compared with controls, but there were no statistically significant differences between mild cases and encephalitis cases. In EV71-infected patients, the counts of white blood cells (P=0.034) and blood glucose concentrations (P=0.042) were raised in A carriers (CA+AA). Among different genotypes of encephalitis cases, the contents of cerebrospinal fluid (CSF) showed no significant differences. IFN-γ levels in EV71-infected patients were higher than those in controls (mild group vs. control group, P<0.01; encephalitis group vs. control group, P<0.01;). In encephalitis cases, IFN-γ levels were reduced (P<0.05) in A carriers compared to CC genotype, however, there were no significant differences between genotypes CA and AA (P=0.226). These findings suggest that OAS2 rs739901 5'-flanking C/A genetic polymorphisms involve the susceptibility to EV71 infection, and A allele might be a risk factor of the susceptibility to EV-71 infection.

Chinese cases of early infantile epileptic encephalopathy: a novel mutation in the PCDH19 gene was proved in a mosaic male- case report.

BACKGROUND: The link between the protocadherin-19 (PCDH19) gene and epilepsy suggests that an unusual form of X-linked inheritance affects females but is transmitted through asymptomatic males. Individuals with epilepsy associated with mutations in the PCDH19 gene display generalized or focal seizures with or without fever sensitivity. The clinical manifestation of the condition ranges from mild to severe, resulting in intellectual disability and behavioural disturbance. In the present study, we assessed mutations in the PCDH19 gene and the clinical features of a group of Chinese patients with early infantile epileptic encephalopathy and aimed to provide further insight into the understanding of epilepsy and mental retardation limited to females (EFMR; MIM 300088). CASE PRESENTATION: We described three variations in the PCDH19 gene in Chinese patients with epilepsy who developed generalized seizures occurring in clusters with or without triggering by fever. Candidate genes were screened for mutations that cause epilepsy and related paroxysmal or nervous system diseases in the coding exons and intron-exon boundaries using polymerase chain reaction (PCR) of genomic deoxyribonucleic acid (DNA) followed by sequencing. The variations were sequenced using next-generation sequencing technology and verified with first-generation sequencing. Exome sequencing of a multigene epilepsy panel revealed three mutations in the PCDH19 gene in a mosaic male and two unrelated females. These included a frameshift mutation c.1508_1509insT (p.Thr504HisfsTer19), a missense mutation c.1681C > T (p.Pro561Ser) and a nonsense mutation c.918C > G (p.Tyr306Ter). Of the three mutations in the PCDH19 gene associated with early infantile epileptic encephalopathy, the frameshift variation in a mosaic male is novel and de novo, the missense variation is de novo and is the second ever reported in females, and the nonsense variation was inherited from the paternal line and is the first example discovered in a female. CONCLUSIONS: The results from our current study provide new insight into and perspectives for the molecular genetic link between epilepsy and PCDH19 alterations. Moreover, our new findings of the male mosaic variant broaden the spectrum of PCDH19-related epilepsy and provide a new understanding of this complex genetic disorder.