UNASSIGNED: Chromosomal microarray analysis (CMA) has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children. The aim of this study was to compare the accuracy and value of CMA and karyotyping on diagnosis of chromosomal abnormalities in Fujian province of South China.In the study, 410 clinical samples were collected from pregnant women between March 2015 and December 2016, including 3 villus (0.73%, 3/410), 296 amniotic fluid (72.20%, 296/410), and 111 umbilical cord blood (27.07%, 111/410). All samples were screening for chromosomal abnormalities by both using CMA and karyotyping.The success rate of CMA and karyotyping was 100% (410/410) and 99.27% (407/410), respectively. Sixty-one (14.88%, 61/410) samples were presented with chromosomal abnormalities by using CMA, whereas 47 (11.55%, 47/407) samples were shown with chromosomal abnormalities by using karyotyping. Thirty-one (8.61%, 31/360) samples with normal karyotypes were found to exist chromosomal abnormalities by using CMA. Receiver operating characteristic analysis showed that the area under the curve of karyotyping on the diagnosis of chromosomal abnormalities was 0.90 (95% confidence interval: 0.87-0.93), the sensitivity and specificity was 87.56% and 91.22%, respectively. The area under the curve of CMA on the diagnosis of chromosomal abnormalities was 0.93 (95% confidence interval: 0.90-0.95), with 90.68% sensitivity and 94.40% specificity. Notably, the combination of CMA and karyotyping could improve the diagnosis of chromosomal abnormalities.CMA has a better diagnostic value for screening chromosomal abnormalities, especially for those pregnant women with normal karyotypes. This study has guiding value for prenatal diagnosis in Fujian province of South China.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

MET exon 14 skipping (METex14) is a validated oncogenic driver in lung cancer and MET tyrosine kinase inhibitors are now available as effective clinical treatments. The majority of known METex14 alterations are typical donor/acceptor splicing or ubiquitination site mutations. Herein, two new METex14 variants were detected in two patients with lung adenocarcinoma by targeted next generation sequencing (NGS). Reverse transcription (RT)-based analysis confirmed that these mutations led to MET exon 14 skipping. Our analysis provided evidence for possible targeted therapy options for patients carrying these MET mutations or similar METex14 analogs.

Obesity is the most crucial phenotype in metabolic syndrome (MetS), and waist circumference (WC) and body mass index (BMI) are two common indexes to define obesity. It is an accepted fact that genetic and environmental interaction influence obesity and MetS. Microsatellites are a subcategory of tandem repeats with a length of 1 to 10 nucleotides. Tandem repeats make up repetitive genomic regions. Differences in the number of tandem repeats or their variation (alleles) result in microsatellite polymorphisms. Thus, we attempted to find microsatellite variation associated with WC and BMI in a family-based study. Twelve microsatellite markers were selected to investigate possible genes or chromosomal regions in 91 families with at least one affected MetS. The cut-off values for BMI and WC were considered 25 kg/m2 and 90 cm, respectively. In all members of the families, the strongest association was observed between the marker D11S1304 (allele 1) with both WC and BMI, independently, by the biallelic model in the family-based association test analysis (P < 0.05). Besides, when we compared high- and low-level groups in members with MetS, the markers D8S1743 and D11S1304 (allele 1) showed a strong association with WC (P = 0.0080) and BMI (P = 0.0074), respectively. When the simultaneous detection of the high WC and MetS status was used as a trait, the strongest association was observed with the marker D8S1743 (P = 0.0034). Moreover, when BMI with the high MetS status was used as a trait, the strongest association was observed with the marker D8S1743 (allele 4) (P = 0.0034). The obtained results showed a relationship between obesity and MetS with markers on the selected regions on chromosomes 8 and 11, and to a lesser degree, on chromosome 12.

Core-binding factor (CBF)-acute myeloid leukemia (AML) generally have a favorable prognosis. However, approximately 50% of patients experience disease relapse during or after post-remission therapy. Retrospective studies on autologous hematopoietic cell transplantation (AHCT) have shown improved survival with decreased relapse rate in CBF-AML. In this prospective study, we evaluate the outcomes of AHCT following high-dose cytarabine (HiDAC) consolidation in patients with CBF-AML in first complete remission (CR). Adult patients with CBF-AML achieving first CR after induction chemotherapy were eligible for the study. High-dose chemotherapy before AHCT included intravenous busulfan (3.2 mg/kg/day, days - 7 to - 5) and etoposide (400 mg/m2/day, days - 3 to - 2). Twenty-nine patients, 17 with t(8;21) and 12 with inv(16), underwent AHCT following 2 or 3 courses of HiDAC consolidation. The estimated 5-year overall and disease-free survival rates were between 89.0% and 82.5%, respectively. The cumulative incidences of relapse and non-relapse mortality were between 17.5% and 0%, respectively. Presence of measurable residual disease (MRD) before AHCT and KIT mutation were significantly associated with relapse after transplantation. In conclusion, the post-remission strategy of AHCT following HiDAC consolidation in CBF-AML was feasible and efficacious. Assays for MRD and KIT mutation may guide selection of patients who will benefit from AHCT in CBF-AML in first CR.

Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. DTC is one of the cancers with the highest familial risk suggesting a major role of genetic risk factors, but only few susceptibility loci were identified so far. In order to assess the contribution of known DTC susceptibility loci and to identify new ones, we conducted a multiethnic genome-wide association study (GWAS) in individuals of European ancestry and of Oceanian ancestry from Pacific Islands. Our study included 1554 cases/1973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from seven population-based case-control studies participating to the EPITHYR consortium. All participants were genotyped using the OncoArray-500K Beadchip (Illumina). We confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 and 16q23.2, which were associated with thyroid-stimulating hormone levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. We also observed that the frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans. However, additional GWAS and epidemiological studies in Oceanian populations are needed to fully understand the highest incidence observed in these populations.

The interpretation of radiation dose is an important procedure for both radiological operators and persons who are exposed to background or artificial radiations. Dicentric chromosome assay (DCA) is one of the representative methods of dose estimation that discriminates the aberration in chromosomes modified by radiation. Despite the DCA-based automated radiation dose estimation methods proposed in previous studies, there are still limitations to the accuracy of dose estimation. In this study, a DCA-based automated dose estimation system using deep learning methods is proposed. The system is comprised of three stages. In the first stage, a classifier based on a deep learning technique is used for filtering the chromosome images that are not appropriate for use in distinguishing the chromosome; 99% filtering accuracy was achieved with 2,040 test images. In the second stage, the dicentric rate is evaluated by counting and identifying chromosomes based on the Feature Pyramid Network, which is one of the object detection algorithms based on deep learning architecture. The accuracies of the neural networks for counting and identifying chromosomes were estimated at over 97% and 90%, respectively. In the third stage, dose estimation is conducted using the dicentric rate and the dose-response curve. The accuracies of the system were estimated using two independent samples; absorbed doses ranging from 1- 4 Gy agreed well within a 99% confidential interval showing highest accuracy compared to those in previous studies. The goal of this study was to provide insights towards achieving complete automation of the radiation dose estimation, especially in the event of a large-scale radiation exposure incident.

Soft markers are nonspecific findings detected by ultrasonography during the second trimester that are often transient and nonpathologic but may imply an increased risk of underlying fetal aneuploidy. However, large-scale prospectively stratified studies focusing on the prevalence of chromosomal aberrations, including copy number variants, in fetuses with different types of isolated soft markers have rarely been published in the literature.
This study aimed to investigate clinical outcomes in fetuses with isolated soft markers by single nucleotide polymorphism array with long-term follow-up and to propose a diagnostic algorithm based on specific types of soft markers.
The prevalence of fetal isolated soft markers was 13.2% (7869 of 59,503). A total of 2466 fetuses with ultrasonographic soft markers during the second trimester, which were subjected to single nucleotide polymorphism array with long-term follow-up, were selected in this prospective study over a 5-year period. Soft markers were categorized into 12 groups. The demographic profile and chromosomal microarray analysis detection results were analyzed and compared among different groups.
The overall prevalence of chromosomal aberrations in fetuses with soft markers was 4.3% (107 of 2466), which comprised 40.2% with numeric chromosomal abnormalities, 48.6% with pathogenic copy number variants, and 11.2% with likely pathogenic copy number variants. The incidence of numeric chromosomal abnormalities was significantly higher in multiple soft markers (5.5% vs 1.5%; P=.001) and the thickened nuchal fold group (8.3% vs 1.7%; P=.024). Meanwhile, the incidence of pathogenic copy number variants was significantly higher in multiple soft markers (5.5% vs 2.4%; P=.046) and the short femur length group (6.6% vs 2.2%; P<.0001). The incidences of pathogenic copy number variants in fetuses with isolated echogenic intracardiac focus, enlarged cisterna magna, choroid plexus cysts, echogenic bowel, or single umbilical artery were lower than 1.5%. The normal infant rate in fetuses without chromosomal aberrations was 91.7%; however, it was significantly lower in the mild ventriculomegaly (86.2% vs 93.0%; P<.0001) and short femur length groups (71.4% vs 93.6%; P<.0001).
The potential chromosomal aberrations and clinical prognoses varied widely among different types of isolated soft markers. Pathogenic copy number variants are more often present in specific soft markers, especially when multiple soft markers are found. Thus, a specific soft marker type-based prenatal genetic testing algorithm was proposed.

Prostate cancer is a major health burden, being the second most commonly diagnosed malignancy in men worldwide. Overtreatment represents a major problem in prostate cancer therapy, leading to significant long-term quality-of-life effects for patients and a broad socio-ecological burden. Biomarkers that could facilitate risk stratification of prostate cancer aggressiveness at the time of diagnosis may help to guide clinical treatment decisions and reduce overtreatment. Previous research on genetic variations in prostate cancer has shown that germline copy number variations as well as somatic copy number alterations are commonly present in cancer patients, altering a greater portion of the cancer genome than any other type of genetic variation. To investigate the effect of germline copy number variations on cancer aggressiveness we have compared genome-wide screening data from genomic DNA isolated from the blood of 120 patients with aggressive prostate cancer, 231 patients with non-aggressive prostate cancer and 87 controls with benign prostatic hyperplasia from the Prostate Cancer Study of Austria biobank using the Affymetrix SNP 6.0 array. We could show that patients with an aggressive form of prostate cancer had a higher frequency of copy number variations [mean count of copy number segments (CNS) = 12.9, median count of CNS = 9] compared to patients with non-aggressive prostate cancer (mean count of CNS = 10.4, median count of CNS = 8) or control patients diagnosed with benign prostatic hyperplasia (mean count of CNS = 9.3, median count of CNS = 8). In general, we observed that copy number gain is a rarer event, compared to copy number loss within all three patient groups. Furthermore, we could show a significant effect of copy number losses located on chromosomes 8, 9 and 10 on prostate cancer aggressiveness (P = 0.040, P = 0.037 and P = 0.005, respectively). Applying a cross-validation analysis yielded an area under the curve of 0.63. Our study reports promising findings suggesting that copy number losses might play an important role in the establishment of novel biomarkers to predict prostate cancer aggressiveness at the time of diagnosis. Such markers could be used to facilitate risk stratification to reduce overtreatment of prostate cancer patients.

The inherent capacity of individuals to efficiently repair ionizing radiation induced DNA double strand breaks (DSBs) may be inherited, however, it is influenced by several epigenetic and environmental factors. A pilot study tested whether chronic low dose natural radiation exposure influences the rejoining of initial DNA DSBs induced by a 2 Gy γ-irradiation in 22 individuals from high (>1.5 mGy/year) and normal (≤1.5 mGy/year) level natural radiation areas (H&NLNRA) of Kerala. Rejoining of DSBs (during 1 h at 37 °C, immediately after irradiation) was evaluated at the chromosome level in the presence and absence of wortmannin (a potent inhibitor of DSB repair in normal human cells) using a cell fusion-induced premature chromosome condensation (PCC) assay. The PCC assay quantitates DSBs in the form of excess chromosome fragments in human G0 lymphocytes without the requirement for cell division. A quantitative difference was observed in the early rejoining of DNA DSBs between individuals from HLNRA and NLNRA, with HLNRA individuals showing a higher (P = 0.05) mean initial repair ratio. The results indicate an influence of chronic low dose natural radiation on initial DNA DSB repair in inhabitants of HLNRA of the Kerala coast.