Molecular and phenotypic spectrum of cardio-facio-cutaneous syndrome in Chinese patients.

BACKGROUND: Cardio-facio-cutaneous (CFC) syndrome is a RASopathy subtype that presents with unique craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. This study describes the phenotypic spectrum of CFC in China and its association with CFC syndrome gene variants. RESULTS: Twenty Chinese CFC patients, aged 0.6-9.5 years old, were included in this study and their clinical phenotypic spectrum was compared with that of 186 patients with CFC from non-Chinese ethnicities. All 20 Chinese patients with CFC carried de novo heterozygous BRAF, MAP2K1, and MAP2K2 variants. Two novel variants were detected and consistently predicted to be deleterious using bioinformatic tools. The clinical features of CFC in the Chinese patients included hypertrophic cardiomyopathy (2/20, 10%), pulmonary valve stenosis (2/20, 10%), curly or sparse hair (7/20, 35%), epilepsy (1/20, 5%), and hypotonia (10/20, 50%); these features were less frequently observed in Chinese patients than non-Chinese patients (p < 0.05). In contrast, feeding difficulties (19/20, 95%) were more frequently observed in the Chinese patients. Absent eyebrows and severe short stature were more common in patients with BRAF variants than in those with MAP2K1/2 variants. Facial recognition software was used to recognize most CFC patients using artificial intelligence. CONCLUSION: This study identified novel and common variants in our cohort of 20 Chinese patients with CFC. We uncovered differences in clinical features between Chinese and non-Chinese patients and detected genotype-phenotype correlations among the BRAF and MAP2K1/2 variant subgroups. This is the largest cohort of Chinese CFC patients to our knowledge, providing new insights into a subtype of RASopathy.

[Identification of a child with Teebi hypertelorism syndrome 1 due to variant of SPECC1L gene].

OBJECTIVE: To explore the clinical characteristics and genetic basis of a child with Teebi hypertelorism syndrome 1 (TBHS1). METHODS: A child with TBHS1 who was admitted to the Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine on July 13, 2021 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and his parents were collected and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a 13-year-old male, had manifested delayed growth and development. WES results revealed that he has harbored a heterozygous c.1244A>G variant of the SPECC1L gene, which was verified to be de novo in origin. The variant has not been included in the HGMD and gnomAD databases. As predicted by online software including PolyPhen-2, SIFT, and Mutation Taster, the variant may affect the function of protein domain. And PyMOL software has predicted that the structural stability of SPECC1L protein (p.Gln415Arg) might be reduced. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PM6+PM1+PP4+PM2_Supporting+PP3). CONCLUSION: The heterozygous c.1244A>G variant of the SPECC1L gene probably underlay the TBHS1 in this child. Above finding has expanded the genotypic and phenotypic spectrum of the SPECC1L gene and provided a basis for the clinical diagnosis of this child.

A novel heterozygous variant of FOXJ1 in a Chinese female with primary ciliary dyskinesia and hydrocephalus: A case report and literature review.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a type of ciliary dyskinesia that is usually caused by autosomal recessive inheritance and can manifest as recurrent respiratory infections, bronchiectasis, infertility, laterality defects, and chronic otolaryngological disease. Although ependymal cilia, which affect the flow of cerebrospinal fluid in the central nervous system, have much in common with respiratory cilia in terms of structure and function, hydrocephalus is rarely associated with PCD. Recently, variants of Forkhead box J1 (FOXJ1) have been found to cause PCD combined with hydrocephalus in a de novo, autosomal dominant inheritance pattern. METHODS: We performed DNA extraction, whole-exome sequencing (WES) analysis, and mutation analysis of FOXJ1 and analyzed the patient's clinical and genetic data. RESULTS: The patient was a 4-year-old female exhibiting normal growth and development. At 3 years and 2 months of age, the patient experienced hand shaking and weakness in the lower limbs. Cardiac ultrasonography showed a right-sided heart, and cranial magnetic resonance imaging showed obstructive hydrocephalus. The nasal nitric oxide level was 54 nL/min. WES indicated a de novo, heterozygous variant of FOXJ1, c.734-735 ins20. This variant was novel, not included in the Human Gene Mutation and Genome Aggregation Database, and likely pathogenic according to the American College of Medical Genetics and Genomics, causing earlier termination of amino acid translation. The patient underwent a neuroendoscopic third ventriculostomy after the diagnosis of obstructive hydrocephalus. Six months after the operation, the patient's motor deficits had improved. CONCLUSION: This is the first report of a de novo, autosomal dominant pattern of FOXJ1 causing PCD combined with hydrocephalus in China. The patient's clinical symptoms were similar to those previously reported. WES confirmed that a novel variant of FOXJ1 was the cause of the PCD combined with hydrocephalus, expanding the spectrum of the genotypes associated with this condition. Physicians should be aware of the correlation of hydrocephalus and PCD and test for FOXJ1 variants.

Empirics on linking industrial agglomeration, energy consumption, residential construction sector growth, and environmental sustainability.

We looked at the long-term and short-term diversified relationships between industrial agglomeration, aggregate energy consumption, residential construction sector growth, and air pollution in China's 30 provincial units from 2004 through 2020. We contributed to the existing knowledge by calculating a holistic air pollution index (API) and applying advanced methods. We also augmented the Kaya identity by including industrial agglomeration and residential construction sector growth in the baseline framework. Based on empirical results: First, we revealed long-term stability among our covariates through panel cointegration analysis. Second, we uncovered a positive bilateral relationship between residential construction sector growth and industrial agglomeration in the long and short term. Third, we unfolded a unilateral positive correlation emerging from aggregate energy consumption to API, displaying the greatest influence in the east zone of China. Fourth, we observed a unilateral positive connection stemming from industrial agglomeration and residential construction sector growth to aggregate energy consumption and API in the long- and short-term dimensions. Finally, the linking nature was homogeneously prevailing across the long term and short term; however, the long-term impact size outweighed that of the short term. Given our empirical results, useful policy insights are discussed to provide the readers with a take-home message for substantiating sustainable development goals.

Genotypic and phenotypic features of dyslipidemia in a sample of pediatric patients in China.

BACKGROUND: Dyslipidemia, especially hypercholesterolemia is of significant clinical interest. Precise diagnosis is not paid enough attention to about the management of pediatric patients with hypercholesterolemia, which is especially apparent in China. Given this, we designed this study to confirm the specific molecular defects associated with hypercholesterolemia using whole-exome sequencing (WES) to be helpful for precise diagnosis and treatment. METHODS: Pediatric patients were enrolled using specific criteria and their clinical information were recorded for later evaluation in conjunction with the WES completed for each of these patients. RESULTS: Our criteria allowed for the initial enrollment of 35 patients, 30 of whom (aged 1.02-12.99 years) underwent successful genetic sequencing and clinical investment. Positive results were obtained in 63.33% (19/30) of these patients. We identified 25 variants in 30 pediatric patients with persistent hypercholesterolemia, seven of them were novel and variants in LDLR and ABCG5/ABCG8 ranks first and second, respectively. Further analysis revealed that the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and lipoprotein (a) were higher in patients with positive genetic results. CONCLUSION: Our study enriched the genetic and phenotypic spectra for hypercholesterolemia in young patients. Genetic testing is important for the prognostics and treatment of pediatric patients. Heterozygous ABCG5/8 variants may be underestimated in pediatric patients with hypercholesterolemia.

Effect of oridonin in reversing cisplatin resistance in melanoma cells and its mechanism / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探讨冬凌草甲素（Ori）逆转人黑色素瘤细胞顺铂（DDP）耐药的作用及其机制。方法：分别将黑色素瘤DDP耐药细胞A375/DDP和M14/DDP分为对照组、2 μmol/L Ori组、4 mg/L DDP组和2 μmol/L Ori+4 mg/L DDP组。CCK-8法、Transwell实验、Annexin Ⅴ-FITC/PI染色流式细胞术分别检测各组细胞的增殖活力、侵袭和迁移能力及凋亡水平，透射电子显微镜观察自噬小体，免疫荧光染色法观察微管相关蛋白轻链3（LC3）点状结构，WB法检测A375/DDP细胞自噬相关蛋白Beclin-1、p62、LC3Ⅱ和LC3Ⅰ的表达。结果: 与4 mg/L DDP组相比，2 μmol/L Ori+4 mg/L DDP组细胞增殖活力、迁移和侵袭能力均显著下降（均P<0.01），凋亡水平显著升高（P<0.01）。4 mg/L DDP组细胞中可见大量自噬小体以及LC3点状染色，但2 μmol/L Ori+4 mg/L DDP组仅可见少量。与对照组相比，4 mg/L DDP组细胞中Beclin-1和LC3Ⅱ/LC3Ⅰ的蛋白表达水平均显著升高（均P<0.01），p62的蛋白表达水平显著降低（P<0.05或P<0.01）；与4 mg/L DDP组相比，2 μmol/L Ori+4 mg/L DDP组细胞中Beclin-1和LC3Ⅱ/LC3Ⅰ的表达水平均显著降低（均P<0.01），p62的表达水平显著升高（P<0.05）。结论: Ori可增加耐药黑色素瘤细胞对DDP的敏感性，此作用可能与其抑制DDP引起的细胞自噬有关。

A novel CEP57 variant associated with mosaic variegated aneuploidy syndrome in a Chinese female presenting with short stature, microcephaly, brachydactyly, and small teeth.

BACKGROUND: Mosaic variegated aneuploidy (MVA) syndrome is a rare, autosomal recessive genetic disease. Here, we report an ultra-rare case of MVA syndrome associated with a CEP57 variant. METHODS: We retrospectively analyzed the clinical data of a 9-year-old female patient and surveyed her family members. Whole-exome sequencing and karyotype analysis were performed; suspected mutations were verified using Sanger sequencing. RESULTS: The patient presented with intrauterine growth restriction, short stature, microcephaly, facial dysmorphism, brachydactyly, and small teeth, and she showed unsatisfactory response to GH replacement therapy. Laboratory tests revealed high insulin-like growth factor-1 levels. Karyotype analysis of the peripheral blood showed mosaic variegated aneuploidies. Whole-exome and Sanger sequencing revealed a novel homozygous nonsense variant, NM_014679.4: c.312 T > G, in CEP57 that leads to translation termination (p.Tyr104*). The parents were heterozygous carriers of the identified variant. CONCLUSION: This study presents an ultra-rare case of CEP57-driven MVA syndrome, identifying a novel homozygous nonsense variant of CEP57 (p.Tyr104*). Our findings enrich the CEP57 mutational spectrum and emphasize the importance of genetic testing in patients with microcephaly and short stature. Furthermore, we conclude that growth hormone treatment is ineffective in such patients.