[Genetic analysis of a Chinese pedigree with 6q26q27 microduplication and 15q26.3 microdeletion].

OBJECTIVE: To explore the genetic basis for a Chinese pedigree with 6q26q27 microduplication and 15q26.3 microdeletion. METHODS: A fetus with a 6q26q27 microduplication and a 15q26.3 microdeletion diagnosed at the First Affiliated Hospital of Wenzhou Medical University in January 2021 and members of its pedigree were selected as the study subject. Clinical data of the fetus was collected. The fetus and its parents were analyzed by G-banding karyotyping and chromosomal microarray analysis (CMA), and its maternal grandparents were also subjected to G-banding karyotype analysis. RESULTS: Prenatal ultrasound had indicated intrauterine growth retardation of the fetus, though no karyotypic abnormality was found with the amniotic fluid sample and blood samples from its pedigree members. CMA revealed that the fetus has carried a 6.6 Mb microduplication in 6q26q27 and a 1.9 Mb microdeletion in 15q26.3, and his mother also carried a 6.49 duplication and a 1.867 deletion in the same region. No anomaly was found with its father. CONCLUSION: The 6q26q27 microduplication and 15q26.3 microdeletion probably underlay the intrauterine growth retardation in this fetus.

Heterozygous pathogenic variants in CWF19L1 in a Chinese family with spinocerebellar ataxia, autosomal recessive 17.

BACKGROUND: CWF19L1 is responsible for spinocerebellar ataxia, autosomal recessive 17, which presents with cerebellar ataxia, and atrophy. Here, we report novel compound heterozygous variants of CWF19L1 in a Chinese family with progressive ataxia and mental retardation of unknown etiology by analyzing clinical characteristics and genetic variations. METHODS: Clinical profiles and genomic DNA extracts of family members were collected. Whole-exome and Sanger sequencing were performed to detect associated genetic variants. Pathogenicity prediction and conservation analysis of the identified variants were performed using bioinformatics tools. RESULTS: We identified heterozygous variants at the invariant +2 position (c.1555_c.1557delGAG in exon 14 and c.1070G > T in exon 11) of the CWF19L1 gene. Two novel heterozygous variants of the CWF19L1 gene were identified in the CWF19L1 gene associated with autosomal recessive cerebellar ataxia. CONCLUSION: Our results suggest that CWF19L1 variants may be a novel cause of recessive ataxia with developmental delay. Whole-exome sequencing is an efficient tool for screening variants associated with the disease. This case report may help diagnose and identify the causes of other ataxias, leading to novel therapies, especially in China. This finding enriches the variant spectrum of the CWF19L1 gene and lays the foundation for future studies on the correlation between genotype and phenotype.

A Genetic Variant in FIGN Gene Reduces the Risk of Congenital Heart Disease in Han Chinese Populations.

Congenital heart disease (CHD) is one of the most common birth anomalies worldwide. Folate deficiency is an independent risk factor for CHD. Genome-wide association studies (GWAS) revealed that human folate level could be significantly influenced by fidgetin (FIGN), methylenetetrahydrofolate reductase (MTHFR), prickle homolog 2 (PRICKLE2), synaptotagmin 9 (SYT9), gamma-aminobutyric acid B receptor 2 (GABBR2), and alkaline phosphatase (ALPL) genes. The association between the above-mentioned six variants and CHD was examined in the two independent case-control studies in a total of 868 CHD patients and 931 healthy controls. Our results showed that the G > C (rs2119289) variant in intron 4 of FIGN led to a significant reduction of CHD susceptibility in both the separate and combined case-control studies (allele distribution P < 0.001, genotype distribution P < 0.001). Specifically, by analyzing the combined samples, we observed that the risks of CHD in individuals carrying the heterozygous G/C and homozygous C/C genotypes were reduced by 45% (adjusted OR 0.55, 95% CI 0.47-0.67) and 66% (adjusted OR 0.34, 95% CI 0.23-0.50), respectively, in comparison with individuals carrying the wild-type G/G genotype. Our findings have demonstrated that the C allele of variant rs2119289 of FIGN gene is an important genetic marker for decreased CHD risk. Considering that the rs2119289 of FIGN gene is related to the appropriate folate level, FIGN might play an important role in CHD by upregulating plasma folate concentration during embryo heart development. This work provides a new insight for risk assessment of CHD.

Dehydrocostus lactone suppresses ox-LDL-induced attachment of monocytes to endothelial cells.

Atherosclerosis is a cardiovascular disease that affects most people to at least some extent by old age. Many factors contribute to atherogenesis, and although it is extremely common, the mechanisms behind the pathogenesis of the disease remain poorly understood. Endothelial dysfunction is thought to be one of the main causes of atherosclerosis along with numerous other factors, such as oxidative stress and proinflammatory cytokine upregulation. The culmination of the complications that lead to atherogenesis is the formation of a fatty plaque on the intima of the arterial endothelium. In this study, we explore these aspects and others in regard to the treatment potential of dehydrocostus lactone (DHL), which is naturally occurring in certain flora such as the Saussurea lappa costus plant. Having long been used in traditional Chinese medicine, the effects of this plant are only just beginning to be studied by modern science. Among our most noteworthy findings are that DHL exerts an inhibitory effect against the increased expression of VCAM-1 and E-selectin induced by exposure to oxidized low-density lipoprotein (ox-LDL), which has been linked to the development and progression of atherosclerosis. The introduction of DHL also significantly diminished the downstream effects of VCAM-1 and E-selectin, such as the attachment of monocytes to the endothelium and the release of proinflammatory cytokines and chemokines, including TNF-α, MCP-1, and HMGB1. Furthermore, DHL is capable of rescuing the expression of KLF2, an important regulator of VCAM-1 and E-selectin expression. Together, our findings demonstrate the potential of DHL as a prophylactic or therapeutic treatment against ox-LDL-induced atherosclerosis via inhibition of the attachment of monocytes to endothelial cells.

Risk factors and outcomes of macrosomia in China: a multicentric survey based on birth data.

OBJECTIVE: To investigate the risk factors and outcomes of macrosomia in China. METHODS: This was a multicenter, retrospective cohort study conducted in China. 178 709 singletons weighing ≥ 2500 g with gestational ages of 37-44 weeks were included. We compared the macrosomia group (with birth weight (BW) ≥ 4000 g) with the nornosomic control group (weighting 2500-3999 g). RESULTS: The total prevalence of macrosomia was 8.70%. The strongest risk factors correlated with macrosomia were maternal obesity and gestational diabetes mellitus (GDM). The risks of obstetric and neonatal complications increased when infants had a BW of ≥4000 g. CONCLUSIONS: Obesity and GDM are the most prominent risk factors for macrosomia, and macrosomia is associated with adverse maternal and neonate outcomes. Therefore, monitoring and controlling maternal weight and blood glucose could decrease the prevalence of macrosomia or improve its poor outcomes.

Homocysteine inhibits neural stem cells survival by inducing DNA interstrand cross-links via oxidative stress.

Elevated plasma levels of homocysteine have been implicated in neurodevelopmental and neurodegenerative disorders in human studies. Although the molecular mechanisms underlying the effects of homocysteine (Hcy) cytotoxicity on the nervous system are not yet fully unknown, induction of DNA interstrand cross-links and inhibition of neural stem cells (NSCs) survival may be involved. The objective of our study was to investigate the effects of Hcy on DNA interstrand cross-links in NSCs, and to explore its possible mechanisms. We also found that Hcy induced cell DNA damage on a dose-dependent manner and evoked reactive oxidative species (ROS) production, leading to elevated apoptosis in NSCs. Moreover, Hcy exposure activated the Fanconi anemia (FA) pathway, which was characterized by increases in monoubiquitination of Fanci and Fancd2 and enhancement of the interaction between above two proteins. On contrary, N-Acety-l-Cysteine (NAC) decreased Hcy-evoked ROS production and significantly ameliorated DNA damage and improved cell survival. These data suggest that Hcy may play a role in the pathogenesis of neurological diseases via a molecular mechanism that induces DNA interstrand cross-links via oxidative stress and involves in negative regulation of NSCs survival.