High-frequency disease-causing alleles exist, but their number is rather small. This study aimed to interpret and reclassify common pathogenic (P) and likely pathogenic (LP) variants in ClinVar and ...to identify indicators linked with reclassification. We analyzed P/LP variants without conflicting interpretations in ClinVar. Only variants with an allele frequency exceeding 0.5% in at least one ancestry in gnomAD were included. Variants were manually interpreted according to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Of 326 variants retrieved, 217 variants in 173 genes were selected for curation. Overall, 87 (40%) variants were downgraded to benign, likely benign or variant of uncertain significance. Five variants (2%) were found to be more likely to be risk factors. Most of the reclassifications were of variants with a low rank, an older classification, a higher allele frequency, or which were collected through methods other than clinical testing. ClinVar provides a universal platform for users who intend to share the classification variants, resulting in the improved concordance of variant interpretation. P/LP variants with a high allele frequency should be used with caution. Ongoing improvements would further improve the practicability of ClinVar database.
There are remarkable disparities among patients of different races with prostate cancer; however, the mechanism underlying this difference remains unclear. Here, we present a comprehensive landscape ...of the transcriptome profiles of 14 primary prostate cancers and their paired normal counterparts from the Chinese population using RNA-seq, revealing tremendous diversity across prostate cancer transcriptomes with respect to gene fusions, long noncoding RNAs （long ncRNA）, alternative splicing and somatic mutations. Three of the 14 tumors （21.4%） harbored a TM- PRSS2-ERG fusion, and the low prevalence of this fusion in Chinese patients was further confirmed in an additional tumor set （10/54=18.5%）. Notably, two novel gene fusions, CTAGE5-KHDRBS3 （20/54=37%） and USP9Y-TTTY15 （19/54=35.2%）, occurred frequently in our patient cohort. Further systematic transcriptional profiling identified nu- merous long ncRNAs that were differentially expressed in the tumors. An analysis of the correlation between expres- sion of long ncRNA and genes suggested that long ncRNAs may have functions beyond transcriptional regulation. This study yielded new insights into the pathogenesis of prostate cancer in the Chinese population.
Spinal muscular atrophy (SMA) is one of the most common and severe genetic diseases. SMA carrier screening is an effective way to identify couples at risk of having affected children. Next-generation ...sequencing (NGS)-based expanded carrier screening could detect SMN1 gene copy number without extra experiment and with high cost performance. However, its performance has not been fully evaluated. Here we conducted a systematic comparative study to evaluate the performance of three common methods. 478 samples were analyzed with multiplex ligation probe amplification (MLPA), real-time quantitative polymerase chain reaction (qPCR) and NGS, simultaneously. Taking MLPA-based results as the reference, for 0 copy, 1 copy and ≥ 2 copy SMN1 analysis with NGS, the sensitivity, specificity and precision were all 100%. Using qPCR method, the sensitivity was 100%, 97.52% and 94.30%, respectively; 98.63%, 95.48% and 100% for specificity; and 72.72%, 88.72% and 100% for precision. NGS repeatability was higher than that of qPCR. Moreover, among three methods, NGS had the lowest retest rate. Thus, NGS is a relatively more reliable method for SMN1 gene copy number detection. In expanded carrier screening, compared with the combination of multiple methods, NGS method could reduce the test cost and simplify the screening process.
Maize kernel oil is a valuable source of nutrition. Here we extensively examine the genetic architecture of maize oil biosynthesis in a genome-wide association study using 1.03 million SNPs ...characterized in 368 maize inbred lines, including 'high-oil' lines. We identified 74 loci significantly associated with kernel oil concentration and fatty acid composition (P < 1.8 × 10(-6)), which we subsequently examined using expression quantitative trait loci (QTL) mapping, linkage mapping and coexpression analysis. More than half of the identified loci localized in mapped QTL intervals, and one-third of the candidate genes were annotated as enzymes in the oil metabolic pathway. The 26 loci associated with oil concentration could explain up to 83% of the phenotypic variation using a simple additive model. Our results provide insights into the genetic basis of oil biosynthesis in maize kernels and may facilitate marker-based breeding for oil quantity and quality.
This paper proposes an adaptive fault‐tolerant control (FTC) method for hypersonic vehicle (HSV) with unexpected centroid shift, actuator fault, time‐varying full state constraints, and input ...saturation. The occurrence of unexpected centroid shift has three main effects on the HSV system, which are system uncertainties, eccentric moments, and variation of input matrix. In order to ensure the time‐varying state constraints, a novel attitude state constraint control strategy, to keep the safe flight of HSV, is technically proposed by a time‐varying state constraint function (TVSCF). A unified controller is designed to handle the time‐varying state constraints according to the proposed TVSCF. Then, the constrained HSV system can be transformed into a novel free‐constrained system based on the TVSCF. For the variation of system input matrix, input saturation and actuator fault, a special Nussbaum‐type function is designed to compensate for those time‐varying nonlinear terms. Additionally, the auxiliary systems is designed to compensate the constraint of system control inputs. Then, it is proved that the proposed control scheme can guarantee the boundedness of all closed‐loop signals based on the Lyapunov stability theory. At last, the simulation results are provided to demonstrate the effectiveness of the proposed fault‐tolerant control scheme.
In this article, an adaptive fault‐tolerant controller is proposed for hypersonic vehicles that experence unexpected centroid shift, actuator faults, time‐varying full state constraints, and input saturation. To ensure the time‐varying state constraints and ensure safe flight, a novel attitude state constraint control strategy is proposed using a time‐varying state constraint function. For variations in the syetem input matrix, input saturation, and actuator faults, a special Nussbaum‐type function is designed to compensate for those time‐varying nonlinear terms. In addition, an auxiliary system is designed to compensate for the constraints of the system control input.
The benefits of concurrent newborn hearing and genetic screening have not been statistically proven due to limited sample sizes and outcome data. To fill this gap, we analyzed outcomes of newborns ...with genetic screening results.
Newborns in China were screened for 20 hearing-loss-related genetic variants from 2012 to 2017. Genetic results were categorized as positive, at-risk, inconclusive, or negative. Hearing screening results, risk factors, and up-to-date hearing status were followed up via phone interviews.
Following up 12,778 of 1.2 million genetically screened newborns revealed a higher rate of hearing loss by three months of age among referrals from the initial hearing screening (60% vs. 5.0%, P < 0.001) and a lower rate of lost-to-follow-up/documentation (5% vs. 22%, P < 0.001) in the positive group than in the inconclusive group. Importantly, genetic screening detected 13% more hearing-impaired infants than hearing screening alone and identified 2,638 (0.23% of total) newborns predisposed to preventable ototoxicity undetectable by hearing screening.
Incorporating genetic screening improves the effectiveness of newborn hearing screening programs by elucidating etiologies, discerning high-risk subgroups for vigilant management, identifying additional children who may benefit from early intervention, and informing at-risk newborns and their maternal relatives of increased susceptibility to ototoxicity.
RNA editing is a post-transcriptional event that recodes hereditary information. Here we describe a comprehensive profile of the RNA editome of a male Han Chinese individual based on analysis of ∼767 ...million sequencing reads from poly(A)(+), poly(A)(-) and small RNA samples. We developed a computational pipeline that carefully controls for false positives while calling RNA editing events from genome and whole-transcriptome data of the same individual. We identified 22,688 RNA editing events in noncoding genes and introns, untranslated regions and coding sequences of protein-coding genes. Most changes (∼93%) converted A to I(G), consistent with known editing mechanisms based on adenosine deaminase acting on RNA (ADAR). We also found evidence of other types of nucleotide changes; however, these were validated at lower rates. We found 44 editing sites in microRNAs (miRNAs), suggesting a potential link between RNA editing and miRNA-mediated regulation. Our approach facilitates large-scale studies to profile and compare editomes across a wide range of samples.
Neuroblastoma is an embryonal tumor of the sympathetic nervous system and the most common extracranial tumor of childhood. By sequencing transcriptomes of low- and high-risk neuroblastomas, we ...detected differentially expressed annotated and nonannotated long noncoding RNAs (lncRNAs). We identified a lncRNA neuroblastoma associated transcript-1 (NBAT-1) as a biomarker significantly predicting clinical outcome of neuroblastoma. CpG methylation and a high-risk neuroblastoma associated SNP on chromosome 6p22 functionally contribute to NBAT-1 differential expression. Loss of NBAT-1 increases cellular proliferation and invasion. It controls these processes via epigenetic silencing of target genes. NBAT-1 loss affects neuronal differentiation through activation of the neuronal-specific transcription factor NRSF/REST. Thus, loss of NBAT-1 contributes to aggressive neuroblastoma by increasing proliferation and impairing differentiation of neuronal precursors.
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•Characterization of long noncoding RNA transcriptome of neuroblastoma tumors•NBAT-1 is a biomarker for predicting the clinical outcome of the neuroblastomas•NBAT-1 epigenetically regulates cell proliferation and migration pathways•NBAT-1 is required for neuronal lineage commitment
Pandey et al. identify the long noncoding RNA NBAT-1 as a prognostic biomarker in neuroblastoma through transcriptome sequencing. NBAT-1 loss increases proliferation and impairs differentiation of neuronal precursors leading to more aggressive disease.
Hearing loss is one of the most common birth disorders in humans, with an estimated prevalence of 1-3 in every 1000 newborns. This study investigates the molecular etiology of a hearing loss cohort ...using a stepwise strategy to effectively diagnose patients and address the challenges posed by the genetic heterogeneity and variable mutation spectrum of hearing loss. In order to target known pathogenic variants, multiplex PCR plus next-generation sequencing was applied in the first step; patients which did not receive a diagnosis from this were further referred for exome sequencing. A total of 92 unrelated patients with nonsyndromic hearing loss were enrolled in the study. In total, 64% (59/92) of the patients were molecularly diagnosed, 44 of them in the first step by multiplex PCR plus sequencing. Exome sequencing resulted in eleven diagnoses (23%, 11/48) and four probable diagnoses (8%, 4/48) among the 48 patients who were not diagnosed in the first step. The rate of secondary findings from exome sequencing in our cohort was 3% (2/58). This research presents a molecular diagnosis spectrum of 92 non-syndromic hearing loss patients and demonstrates the benefits of using a stepwise diagnostic approach in the genetic testing of nonsyndromic hearing loss.
To investigate the predictive value of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor tyrosine kinase ...inhibitors (EGFR-TKIs).
We conducted a systemic search of PubMed, EMBASE, and the Cochrane Library from 1 January 2000 to 30 August 2020, to identify related studies. We combined the hazard ratio (HR) and 95% confidence interval (CI) to assess the correlation of PD-L1 expression with progression-free survival (PFS) and overall survival (OS). We assessed the quality of the included studies by the Newcastle-Ottawa Scale (NOS). We performed subgroup analyses based on immunohistochemistry (IHC) scoring system, IHC antibodies, sample size, countries, and survival analysis mode. Sensitivity analysis and evaluation of publication bias were also performed.
Twelve studies including 991 patients met the criteria. The mean NOS score was 7.42 ± 1.19. Patients with high PD-L1 expression was associated with poorer PFS (HR = 1.90; 95% CI = 1.16-3.10; P = 0.011), while there was no association between PD-L1 expression and OS (HR = 1.19; 95% CI = 0.99-1.43; P = 0.070). Subgroup analysis prompted IHC scoring systems, IHC antibodies, and sample size have important effects on heterogeneity. The pooled results were robust according to the sensitivity analysis.
The result of this meta-analysis suggested that PD-L1 expression might be a predictive biomarker for EGFR-mutant non-small cell lung cancer treated with EGFR-TKIs.
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