[Application of copy number variation sequencing in patients with intellectual disability/developmental delay and autistic spectrum disorder].

OBJECTIVE: To assess the value of copy number variation sequencing (CNV-seq) for the diagnosis of children with intellectual disability (ID), developmental delay (DD), and autistic spectrum disorder (ASD). METHODS: Forty patients with ID/DD/ASD referred to Nanshan Maternity and Child Health Care Hospital from September 2018 to January 2022 were enrolled. G-banded karyotyping analysis was carried out for the patients. Genomic DNA was extracted from peripheral blood samples and subjected to CNV-Seq analysis to detect chromosome copy number variations (CNVs) in such patients. ClinVar, DECIPHER, OMIM and other database were searched for data annotation. RESULTS: Among the 40 patients (including 30 males and 10 females), 16, 15 and 6 were diagnosed with ID, DD and ASD, respectively. One patient had combined symptoms of ID and DD, whilst the remaining two had combined ID and ASD. Four patients were found with abnormal karyotypes, including 47,XY,+mar, 46,XY,inv(8)(p11.2q21.2), 46,XX,del(5)(p14) and 46,XX[76]/46,X,dup(X)(p21.1q12). Chromosome polymorphism was also found in two other patients. CNV-seq analysis has detected 32 CNVs in 20 patients (50.0%, 20/40). Pathogenic CNVs were found in 10 patients (25.0%), 15 CNVs of uncertain clinical significance were found in 12 patients (30.0%), and 7 likely benign CNVs were found in 4 patients (10.0%). CONCLUSION: Chromosome CNVs play an important role in the pathogenesis of ID/DD/ASD. CNV-seq can detect chromosomal abnormalities including microdeletions and microduplications, which could provide a powerful tool for revealing the genetic etiology of ID/DD/ASD patients.

Feingold syndrome type 2 in a patient from China.

Feingold syndrome type 2 (FGLDS2, MIM614326) is a genetic congenital malformation syndrome, caused by germline heterozygous deletion of MIR17HG on chromosome 13q31, which is extremely rare worldwide. To date, less than 25 patients have been described in the literature. Here, we report on a 3-year-old girl presented with hip dysplasia, polysyndactyly of the left thumb, brachymesophalangy of the fifth digit, microcephaly, intellectual disability, and growth delay. This is likely to be the first case of Feingold syndrome type 2 ever discovered among Chinese population. Through genetic testing and pedigree analysis, she was identified to have a de novo 4.8-Mb microdeletion at chromosome 13q31.3-q32.1, encompassing MIR17HG, GPC5, and GPC6. Additionally, we detected two common compound heterozygous variants (c.919-2A>G and c.147C>G) in SLC26A4 encoding pendrin protein, as well as a novel heterozygous variant c.985_988del in COMP encoding cartilage oligomeric matrix protein. This case report aims to analyze the microdeletion and the three types of variant detected in the patient, and to explore the association between the genotype and phenotype in patients with Feingold syndrome type 2, which may contribute to further understanding and future diagnosis of this disorder.

Deferoxamine synergizes with transforming growth factor-β signaling in chondrogenesis

Abstract Osteoarthritis, also known as degenerative arthritis or degenerative joint disease, is an epidemic disease that affects millions of people worldwide. Despite extensive recent work on the cellular biology of osteoarthritis, the precise mechanisms involved are still poorly understood and there is no effective treatment for this disease. The role of transforming growth factor-beta (TGF-β) in promoting chondrogenesis and inducing the expression of cartilage-specific extracellular matrix molecules to form cartilage is well-established. Historically, TGF-β has been considered to prevent osteoarthritis, but recent work suggests that TGF-β overexpression accelerates the progression of osteoarthritis in vivo. Clinically, it is therefore important to limit TGF-β expression while still providing effective treatment of osteoarthritis. One possible approach to achieve this effect would be to use a combination of TGF-β with other small molecular chemical compounds. Hypoxia promotes chondrogenesis and the usefulness of deferoxamine, a chelating agent that mimics hypoxia, in stimulating chondrogenesis has been investigated in clinical trials. In this study, we investigated the role of deferoxamine in TGF-β-induced chondrogenesis in pre-chondrogenic cells and examined whether deferoxamine synergizes with the TGF-β signaling pathway to promote chondrocyte differentiation.

Deferoxamine synergizes with transforming growth factor-ß signaling in chondrogenesis.

Osteoarthritis, also known as degenerative arthritis or degenerative joint disease, is an epidemic disease that affects millions of people worldwide. Despite extensive recent work on the cellular biology of osteoarthritis, the precise mechanisms involved are still poorly understood and there is no effective treatment for this disease. The role of transforming growth factor-beta (TGF-ß) in promoting chondrogenesis and inducing the expression of cartilage-specific extracellular matrix molecules to form cartilage is well-established. Historically, TGF-ß has been considered to prevent osteoarthritis, but recent work suggests that TGF-ß overexpression accelerates the progression of osteoarthritis in vivo. Clinically, it is therefore important to limit TGF-ß expression while still providing effective treatment of osteoarthritis. One possible approach to achieve this effect would be to use a combination of TGF-ß with other small molecular chemical compounds. Hypoxia promotes chondrogenesis and the usefulness of deferoxamine, a chelating agent that mimics hypoxia, in stimulating chondrogenesis has been investigated in clinical trials. In this study, we investigated the role of deferoxamine in TGF-ß-induced chondrogenesis in pre-chondrogenic cells and examined whether deferoxamine synergizes with the TGF-ß signaling pathway to promote chondrocyte differentiation.

Podocalyxin promotes cisplatin chemoresistance in osteosarcoma cells through phosphatidylinositide 3-kinase signaling.

Osteosarcoma (OS) is the most common type of primary bone malignancy. The use of multiagent, intensive chemotherapy has markedly improved the long­term survival rate of patients with OS. However, chemoresistance continues to be the principal reason for poor survival and disease recurrence in patients with OS. Innate or acquired resistance to cisplatin, which is one of the most effective drugs against OS, is common. Understanding the molecular basis underlying cisplatin chemoresistance in OS cells may serve as a basis for the identification of novel therapeutic targets and biomarkers. High expression levels of podocalyxin (PCX) have been shown to be correlated with poor outcome in various types of cancer. A recent study suggested that PCX may contribute to cancer chemoresistance. The present study aimed to explore the role of PCX in OS by determining its effects on cisplatin chemoresistance in OS cells. Stable overexpression and knockdown of PCX were performed in MG­63 and U2OS human OS cell lines. Overexpression of PCX in the two cell lines significantly increased the half maximal inhibitory concentration (IC50) of cisplatin, cell colony formation, phosphatidylinositide 3­kinase (PI3K) activity and Akt phosphorylation at serine 473, and decreased cisplatin­induced cell apoptosis. Furthermore, the effects of PCX were largely attenuated by treatment with the selective PI3K inhibitor BKM120. Conversely, knockdown of PCX expression markedly decreased the IC50 of cisplatin, cell colony formation, PI3K activity and Akt phosphorylation at serine 473, and increased cisplatin­induced cell apoptosis. In conclusion, the present study was the first, to the best of our knowledge, to provide evidence that PCX promotes cisplatin chemoresistance in OS cells through a PI3K­dependent mechanism. The results of the present study provided novel insight not only into the functional role of PCX in cancer, but also into the molecular mechanisms underlying OS chemoresistance.