Prenatal diagnosis of skeletal dysplasias using whole exome sequencing in China.

BACKGROUND: Skeletal dysplasias account for nearly 10% of fetal structural malformations detected by ultrasonography. This clinically heterogeneous group of genetic anomaly includes at least 461 genetic skeletal disorders with extreme clinical, phenotypic, and genetic heterogeneities, thus, significantly complicates accurate diagnosis. Researches have used whole exome sequencing (WES) for prenatal molecular diagnoses of skeletal dysplasias, however, data are still limited. METHODS: DNA extracted from umbilical cord blood or amniocytes from fetuses suspected of skeletal dysplasias based on ultrasound evaluations were analyzed by WES. Blood samples were taken from the parents of the positive fetuses for co-segregation analysis using Sanger sequencing. RESULT: Definitive molecular diagnosis was made in 6/8 (75%) cases, comprised of 5 de novo disease-causing changes in 3 genes (FGFR3, COL2A1, and COL1A2) and one proband with a biallelic deficiency for Lamin B Receptor(LBR),and including 3 novel variants. All fetuses had no detectable copy number variation (CNV) from sequencing results. CONCLUSIONS: Our study suggests that WES is an efficient approach for prenatal diagnosis of fetuses suspected of skeletal abnormalities and contributes to parental genetics counseling and pregnancy management.

Novel SPEG variant cause centronuclear myopathy in China.

BACKGROUND: Centronuclear myopathy (CNM), a subtype of congenital myopathy (CM), is a group of clinical and genetically heterogeneous muscle disorders. Centronuclear myopathy is a kind of disease difficult to diagnose due to its genetic diversity. Since the discovery of the SPEG gene and disease-causing variants, only a few additional patients have been reported. METHODS: A radiograph test, ultrasonic test, and biochemical tests were applied to clinical diagnosis of CNM. We performed trio medical exome sequencing of the family and conservation analysis to identify variants. RESULTS: We report a pair of severe CNM twins with the same novel homozygous SPEG variant c. 8710A>G (p.Thr2904Ala) identified by clinical trio medical exome sequencing of the family and conservation analysis. The twins showed clinical symptoms of facial weakness, hypotonia, arthrogryposis, strephenopodia, patent ductus arteriosus, and pulmonary arterial hypertension. CONCLUSIONS: Our report expands the clinical and molecular repertoire of CNM and enriches the variant spectrum of the SPEG gene in the Chinese population and helps us further understand the pathogenesis of CNM.

Identification of miRNA-Based Signature as a Novel Potential Prognostic Biomarker in Patients with Breast Cancer.

To identify the novel, noninvasive biomarkers to assess the outcome and prognosis of breast cancer (BC), patients with high sensitivity and specificity are greatly desired. Herein, the miRNA expression profile and matched clinical features of BC patients were extracted from The Cancer Genome Atlas (TCGA) database. The preliminary candidates were screened out by the univariate Cox regression test. Then, with the help of LASSO Cox regression analysis, the hsa-let-7b, hsa-mir-101-2, hsa-mir-135a-2, hsa-mir-22, hsa-mir-30a, hsa-mir-31, hsa-mir-3130-1, hsa-mir-320b-1, hsa-mir-3678, hsa-mir-4662a, hsa-mir-4772, hsa-mir-493, hsa-mir-556, hsa-mir-652, hsa-mir-6733, hsa-mir-874, and hsa-mir-9-3 were selected to construct the overall survival (OS) predicting signature, while the hsa-mir-130a, hsa-mir-204, hsa-mir-217, hsa-mir-223, hsa-mir-24-2, hsa-mir-29b-1, hsa-mir-363, hsa-mir-5001, hsa-mir-514a-1, hsa-mir-624, hsa-mir-639, hsa-mir-659, and hsa-mir-6892 were adopted to establish the recurrence-free survival (RFS) predicting signature. Referring to the median risk scores generated by the OS and RFS formulas, respectively, subgroup patients with high risk were strongly related to a poor OS and RFS revealed by Kaplan-Meier (K-M) plots. Meanwhile, receiver operating curve (ROC) analysis validated the accuracy and stability of these two signatures. When stratified by clinical features, such as tumor stage, age, and molecular subtypes, we found that the miRNA-based OS and RFS classifiers were still significant in predicting OS/RFS and showed the best predictive values than any other features. Besides, functional prediction analyses showed that these targeted genes of the enrolled miRNAs were enriched in cancer-associated pathways, such as MAPK/RTK, Ras, and PI3K-Akt signaling pathways. In summary, our observations demonstrate that the novel miRNA-based OS and RFS signatures are independent prognostic indicators for BC patients and worthy to be validated by further prospective studies.