Large Cohort Of Chinese Patients Research Articles

Anti-β2GPI domain 1 antibodies stratify high risk of thrombosis and late pregnancy morbidity in a large cohort of Chinese patients with antiphospholipid syndrome

IntroductionAnti-β2GPI-Domain 1 (β2GPI-D1) antibodies are considered to be a pathogenic subset of anti-β2GPI antibodies and have been strongly associated with thrombosis and pregnancy morbidity in patients with antiphospholipid syndrome (APS). We evaluated the clinical utility of anti-β2GPI-D1 IgG antibodies for stratifying the risk of thrombosis and/or pregnancy morbidity (PM) in a cohort of Chinese patients with APS and also assessed its correlation with the Global Anti-Phospholipid Syndrome Score (GAPSS). Materials and methodsSera and plasma from 192 consecutive APS patients, 17 aPL carriers, 193 patients with other systemic autoimmune diseases, and 120 healthy controls were collected and the presence of aCL IgG/IgM, anti-β2GPI IgG/IgM and anti-β2GPI-D1 IgG antibodies were assessed by chemiluminescence assays (CIA). Detection of LAC was performed according to international guidelines with the use of screening, mixing and confirmation tests. Anti-phosphatidylserine-prothrombin (aPS/PT) IgG and IgM antibodies were detected by commercial ELISA kits. ResultsAnti-β2GPI-D1 IgG antibodies showed high specificity (97.12%) and moderate sensitivity (64.32%) for the diagnosis of APS. Anti-β2GPI-D1 antibodies levels were significantly higher in patients with triple aPL positivity than in those with double (P < 0.001) and single positive aPL (P < 0.001) and correlated well with the GAPSS (rho = 0.60, P < 0.001). Anti-β2GPI-D1 antibodies presented with a higher prevalence and higher titers in patients with late pregnancy morbidity (≥10 weeks) and thrombotic APS compared to those with early pregnancy (<10 weeks) morbidity. Higher anti-β2GP1-D1 antibodies titers effectively distinguished APS from other autoimmune diseases. ConclusionThis study suggests a predictive role of anti-β2GPI-D1 IgG antibodies as a strong risk factor for both thrombotic and obstetric APS (OAPS), especially for stratification comparing early PM with late PM and thrombosis.

P4596Long-term outcomes of culprit lesion only versus multi-vessel one-stage intervention in non-ST elevation acute coronary syndrome patients undergoing percutaneous coronary interventioo

Abstract Background It is recommended to base revascularization strategy on the clinical status, comorbidities and lesion characteristics in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). However, the risk and benefit of Culprit Lesion Only (CVO) versus Multi-vessel One-stage Intervention (MVOI) is unclear. We aim to compare the long-term prognosis of NSTE-ACS undergoing CVO and MVOI PCI strategy. Method A total of 4768 consecutive patients with NSTE-ACS who underwent PCI in our hospital in 2013 were enrolled in this study. Patients were divided into CVO group and MVOI group according to whether the culprit vessel was the only target vessel. Prognosis impact on 2-year major adverse cardiovascular and cerebrovascular events (MACCE) is analyzed across 2 groups, including death, cardiac death, myocardial infarction, unplanned revascularization, in-stent thrombosis, stroke and bleeding. Results Compared with CVO group, MVOI patients had generally worse clinical baseline characteristics and angiographic findings, including higher BMI, SYNTAX score, higher proportion of diabetes, hypertension, NSTEMI, tri-vessel disease, total occlusion, etc. Two-year follow-up revealed that MVOI patients have significantly higher rate of unplanned revascularization (10.1% vs. 7.9%, p=0.018), stroke (2.2% vs. 1.3%, p=0.042) and MACCE (14.0% vs. 11.3%, p=0.012). Kaplan-Meier survival analysis yielded similar results. After adjusting for confounding factors by Cox regression analysis, MVOI was shown to be independently associated with higher rate of 2-year in-stent thrombosis (HR = 3.718, 95% CI: 1.125 - 12.293). Two-year Clinical Outcomes CVO (n=3634) MVOI (n=1134) P value All-cause Death 39 (1.1) 13 (1.1) 0.836 Cardiac Death 18 (0.5) 8 (0.7) 0.402 Myocardial Infarction 64 (1.8) 22 (1.9) 0.693 Unplanned Revascularization 287 (7.9) 115 (10.1) 0.018 In-stent Thrombosis 26 (0.7) 12 (1.1) 0.257 Stroke 49 (1.3) 25 (2.2) 0.042 Bleeding 253 (7.0) 67 (5.9) 0.216 MACCE 409 (11.3) 159 (14.0) 0.012 CVO = Culprit Vessel Only; MVOI = Multivessel One-stage Intervention; MACCE = Major Adverse Cardiac and Cerebrovascular Events. Cox Regression Analysis on CVO/MVOI Conclusion In our large cohort of Chinese patients, MVOI strategy for NSTE-ACS patient undergoing PCI was associated with worse 2-year prognosis compared with CVO strategy. MVOI is an independent risk factor for 2-year in-stent thrombosis. Acknowledgement/Funding Ministry of Science and Technology of the People's Republic of China (2016YFC1301301) and National Natural Science Foundation of China (81470486)

Mutation spectrum of the bestrophin-1 gene in a large Chinese cohort with bestrophinopathy

BackgroundBestrophin-1 (BEST1) gene is associated with a wide range of ocular phenotypes, collectively termed as bestrophinopathy. The aim of the current study was to identify the mutation spectrum of BEST1...

New insights from unbiased panel and whole-exome sequencing in a large Chinese cohort with disorders of sex development.

Diagnosis of non-chromosomal type disorders of sex development (DSD) has long been challenging. There is still no research on overview of a large Chinese DSD cohort. To determine the etiologic diagnosis through unbiased large-scale panel sequencing and whole-exome sequencing (WES) within a large Chinese DSD cohort. Patients were recruited according to the inclusion criteria of DSD. The applied panel contains 2742 known disease-causing genes, including all known diagnostic genes for DSD. Targeted panel sequencing (TPS) was performed, and identified candidate variants were verified. Variant pathogenicities were evaluated according to established guidelines. WES was performed for randomly selected negative samples. This study included 125 patients. Seventy-five variants were identified by TPS and 31 variants were reported for the first time. Pathogenic and likely pathogenic variants accounted for 38.7 and 30.7%, respectively. On the basis of clinical certainty, etiologic diagnostic rates of 46.9 and 10.3% were obtained for 46,XY and 46,XX DSD patients, respectively. We reported novel candidate genes (BMPR1B, GNAS, GHR) and regions of copy number variants outside the expected DSD genotype-phenotype correlation and determined a founder mutation (SRD5A2 p.R227Q) in patients with 5α-reductase deficiency. Further WES in randomly selected negative samples identified only one among 14 negative samples as a variant of uncertain significance, indicating that WES did not improve the diagnostic rate. This is the first report of the applying unbiased TPS in a large Chinese cohort of patients with 46,XY and 46,XX DSD. Our findings expand the gene, mutation and phenotype spectra of the rare types of DSD in the Chinese population and provide new insight into the current understanding of the etiologies of DSD.

Molecular findings in children with inherited intrahepatic cholestasis.

Genetic defects account for a substantial proportion of pediatric cholestasis. This study explored the molecular findings in a large cohort of Chinese patients with inherited cholestasis. Between January 2012 and June 2016, 809 Chinese pediatric patients with suspected inherited intrahepatic cholestasis were evaluated by Sanger sequencing and/or panel sequencing. Of the 809 patients, 273 (33.7%) obtained a genetic diagnosis. The rate of positive genetic diagnosis in patients with disease onset at 0-3 month of age was higher than that in patients with disease onset at 4 month of age or later. There were 17 distinct genetic defects diagnosed. The top 4 resulted from mutations in SLC25A13 (44.3%), JAG1 (24.5%), ABCB11 (11.0%), and ATP8B1 (5.9%). All 17 genetic disorders were diagnosed in patients with disease onset at 0-3 months of age; but only 5 were diagnosed in patients with disease onset beyond 4 months of age. A total of 217 distinct pathogenic variants, including 41 novel variants, were identified. Ten recurrent mutations were detected in SLC25A13, ATP8B1, and CYP27A1. They accounted for 48.2% of the total 477 mutant alleles. There were 17 distinct genetic disorders diagnosed in Chinese pediatric patients with inherited cholestasis.

Comprehensive analysis of spectral distribution of a large cohort of Chinese patients with non-syndromic oculocutaneous albinism facilitates genetic diagnosis.

Non‐syndromic oculocutaneous albinism (nsOCA) is a group of genetically heterogeneous autosomal recessive disorders with complete lack or decrease pigmentation in skin, hair, and eyes. TYR, OCA2, TYRP1, SLC45A2, SLC24A5, and LRMDA were reported to cause OCA1‐4 and OCA6‐7, respectively. By sequencing all the known nsOCA genes in 114 unrelated Chinese nsOCA patients combined with In silico analyses, splicing assay, and classification of variants according to the standards and guidelines of American College of Medical Genetics and Genomics, we detected seventy‐one different OCA‐causing variants separately in TYR, OCA2, SLC45A2, and SLC24A5, including thirty‐one novel variants (13 in TYR, 11 in OCA2, and 7 in SLC45A2). This study shows that OCA1 is the most common (75/114) and OCA2 ranks the second most common (16/114) in Chinese. 99 patients of our cohort were caused by variants of all the known nsOCA genes. Cutaneous phenotypes of OCA1, OCA2, and OCA4 patients were shown in this study. The second OCA6 case in China was identified here. These data expand the spectrum of OCA variants as well phenotype and facilitate clinical implement of Chinese OCA patients.

Genetic and Clinical Findings in a Large Cohort of Chinese Patients with Suspected Retinitis Pigmentosa

To characterize the genetic landscape of patients with suspected retinitis pigmentosa (RP) in the Chinese population. Cohort study. A total of 1243 patients of Chinese origin with clinically suspected RP and their available family members (n= 2701) were recruited. All patients and available family members were screened using multigene panel testing (including 586 eye disease-associated genes), followed by clinical variant interpretation. Diagnostic yield, the 17 most commonly implicated genes, age at onset, de novo mutations, and clinical usefulness of genetic testing. Overall, 72.08% of patients received a molecular diagnosis, and the 17 top genes covered 75.63% of diagnostic cases. Diagnostic yield was higher among patients in the early-onset subgroup (≤5 years old, 79.58%) than in the childhood or adolescence-onset subgroup (6-16 years old, 73.74%) and late-onset subgroup (≥17 years old, 65.99%). Moreover, different genes associated with different onset ages and subgroups with different onset ages showed a diverse mutation spectrum. Only 11 de novo mutations (3.18%) were identified. Furthermore, 16.84% of the patients who received a molecular diagnosis had refinement of the initial clinical diagnoses, and the remaining 83.16% received definite genetic subtypes of RP. This large cohort study provides population-based data of the genome landscape of patients with suspected RP in China. The diagnostic yield was significantly higher than that in previous studies, and the mutation spectrum is completely different with other populations. Genetic testing improves the chance to establish a precise diagnosis, identifies features not previously determined, and allows a more accurate refinement of risk to family members. Our results not only expand the existing genotypic spectrum but also serve as an efficient reference for the design of panel-based genetic diagnostic testing and genetic counseling for patients with suspected RP in China.

Unique profiles of targetable genomic alterations and prognosis in young Chinese patients with lung adenocarcinoma

ObjectiveLung adenocarcinoma in young patients is a rare entity, and the targetable genomic alterations (GAs) are poorly studied. In other cancers, it has been demonstrated that young age defines unique disease biology. Here, the association of young age with GAs and prognosis is studied in a large cohort of Chinese patients. MethodsWe retrospectively screened 1000 consecutive patients, and identified 181 patients aged 40 years or younger. GAs were identified by next-generation sequencing (NGS) assay. The clinical and genetic characteristics were analyzed. ResultsAmong younger group, 167(92.3%) patients were diagnosed withadvanced-stage adenocarcinoma, 98(54.1%) were female, 27(14.9%) were smokers, and the median age was 35 years. Targetable GAs which were significantly more common in the younger population (P < 0.001), were associated with young age (P < 0.05). The frequency of ALK translocations, EGFR and KRAS mutations was 37.6%, 34.3% and 6.1%, respectively. Younger patients had a higher prevalence of rare GAs including HER2, ROS1 and MET (P < 0.05). Prognosis for younger patients was similar (median OS of patients with GAs, 23.91 vs 23.67 months, P > 0.05) or better than that for older population (median OS of patients without GAs, 44.28 vs 41.88 months, P < 0.05) according to GAs. Therapy modality was an independent prognostic factor (P < 0.05), and 83% of death rate decreased if given preferred therapy. ConclusionYounger patients with lung adenocarcinoma had unique prevalence of targetable GAs. Comprehensive genotyping including NGS is recommended for personalized therapy and prognosis evaluation in this population.

Testing the role of genetic variation of the MC4R gene in Chinese population in antipsychotic-induced metabolic disturbance

Antipsychotic-induced metabolic disturbance (AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor (MC4R) gene, one of the candidate genes for AIMD, has been under-studied in the Chinese patients. We conducted a pharmacogenetic study in a large cohort of Chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4R in Chinese population by genotyping two SNPs (rs489693 and rs17782313) in 1,991 Chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index (BMI), waist circumference (WC), glucose, triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status (drug-naïve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-naïve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way.

Frequency and factors related to drooling in Chinese patients with multiple system atrophy: a cross-sectional study.

Drooling is a common symptom of neurodegenerative diseases. We aimed to explore the frequency of drooling and its relationship to clinical features in a relatively large cohort of Chinese patients with multiple system atrophy (MSA). We conducted a cross-sectional survey of 143 patients with MSA. Patients with drooling were identified as those with a score ≥ 1 on item 6 of the Unified Parkinson's Disease Rating Scale. Additional scales were used to rate daily functionality, neurologic and cognitive capabilities, levels of anxiety and depression, and sleep quality. These results were compared between patients with and without drooling. The frequency of drooling in this cohort was 59.4% (85/143). Drooling was associated with significantly poorer scores on the Unified MSA Rating Scale (subscore I, subscore II, subscore IV, total score), Pittsburgh Sleep Quality Index, Hamilton Depression Scale, Hamilton Anxiety Scale, and Mini-Mental State Examination. After adjusting for confounders, regression analysis identified two independent risk factors for drooling: parkinsonism-associated MSA (OR 2.54, 95% CI 1.15-5.65) and hypomimia (OR 3.18, 95% CI 1.32-7.68). Drooling is relatively common among Chinese MSA patients, and parkinsonism-associated MSA and hypomimia appear to be independent risk factors for drooling. The severity of this symptom correlates with the presence of severe motor symptoms, anxiety, depression, and sleep disorders.

Clinical and genetic spectrum of sarcoglycanopathies in a large cohort of Chinese patients

BackgroundSarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophy (LGMD2C, LGMD2D, LGMD2E, and LGMD2F) that are caused, respectively, by mutations in the SGCG, SGCA, SGCB, and SGCD genes. Knowledge about the clinical and genetic features of sarcoglycanopathies in Chinese patients is limited. The aims of this study were to investigate in detail the clinical manifestations, sarcoglycan expression, and gene mutations in Chinese patients with sarcoglycanopathies and to identify possible correlations between them.ResultsOf 3638 patients for suspected neuromuscular diseases (1733 with inherited myopathies, 1557 with acquired myopathies, and 348 unknown), 756 patients had next-generation sequencing (NGS) diagnostic panel. Twenty-five patients with sarcoglycanopathies (11.5%) were identified from 218 confirmed LGMDs, comprising 18 with LGMD2D, 6 with LGMD2E, and one with LGMD2C. One patient with LGMD2D also had Charcot-Marie-Tooth 1A. The clinical phenotypes of the patients with LGMD2D or LGMD2E were markedly heterogeneous. Muscle biopsy showed a dystrophic pattern in 19 patients and mild myopathic changes in 6. The percentage of correct prediction of genotype based on expression of sarcoglycan was 36.0% (4 LGMD2D, 4 LGMD2E, and one LGMD2C). There was a statistically significant positive correlation between reduction of α-sarcoglycan level and disease severity in LGMD2D. Thirty-five mutations were identified in SGCA, SGCB, SGCG, and PMP22, 16 of which were novel. Exon 3 of SGCA was a hotspot region for mutations in LGMD2D. The missense mutation c.662G > A (p.R221H) was the most common mutation in SGCA. Missense mutations in both alleles of SGCA were associated with a relative benign disease course. No obvious clinical, sarcoglycan expression, and genetic correlation was found in LGMD2E.ConclusionsThis study expands the clinical and genetic spectrum of sarcoglycanopathies in Chinese patients and provides evidence that disease severity of LGMD2D may be predicted by α-sarcoglycan expression and SGCA mutation.

Detecting pioglitazone use and risk of cardiovascular events using electronic health record data in a large cohort of Chinese patients with type 2 diabetes.

BackgroundPioglitazone may have a protective effect against cardiovascular disease risk among type 2 diabetes (T2D) patients, but evidence from China is lacking. This study investigated the association using electronic health records (EHR) data from a Chinese cohort of T2D patients.MethodsAll T2D patients from the First Affiliated Hospital of Nanjing Medical University who were prescribed at least one oral antidiabetic drug and were aged ≥18 years between 1 July 2005 and 30 June 2017 were eligible for inclusion (n = 71 783). Pioglitazone use was determined in 6‐month study intervals, with outcome events of myocardial infarction (MI), ischemic stroke, and heart failure. Poisson regression was used to estimate adjusted rate ratios (RRs) with 95% confidence intervals (CIs).ResultsIn multivariable analysis adjusted for potential confounders, pioglitazone use, compared with no use, was associated with a significant 39% decreased risk of MI (RR = 0.61; 95% CI = 0.42‐0.90; P = 0.012). Pioglitazone use was also associated with a non‐significant reduction in risk of heart failure or stroke. When MI, heart failure, and stroke were combined as a composite outcome, pioglitazone use was associated with a 30% decrease in risk (RR = 0.70; 95% CI = 0.56‐0.88; P = 0.002).ConclusionsThis study demonstrates that applying informatics tools to a large EHR database could be a good way to efficiently conduct clinical observational research. In addition, the findings validated the favorable effect of pioglitazone on the risk of MI among T2D patients in China, with the use of pioglitazone decreasing the risk of MI among those with T2D.

Clinical and genetic analysis in a large Chinese cohort of patients with X-linked hypophosphatemia.

X-linked Hypophosphatemia (XLH) is caused by loss of function mutations in the PHEX gene. Given the recent availability of a new therapy for XLH, a retrospective analysis of the most recent 261 Chinese patients with XLH evaluated at Peking Union Medical College Hospital was conducted. Clinical, biochemical, radiographic studies, as well as genetic analyses, including Sanger sequencing for point mutations and Multiplex Ligation-dependent Probe Amplification (MLPA) to detect large deletions/duplications were employed. Based on the structure of Neprilysin (NEP), a member of M13 family that includes PHEX, a three-dimensional (3D) model of PHEX was constructed, missense and nonsense mutations were positioned on the predicted structure to visualize relative positions of these two types of variants. Sex differences and genotype-phenotype correlations were also undertaken. Genetic analyses identified 166 PHEX mutations in 261 XLH patients. One hundred and eleven of the 166 mutations were unreported. Four mutational 'hot-spots' were identified in this cohort (P534L, G579R, R747X, c.1645+1 G>A). Missense mutations, but not nonsense mutations, clustered in the two putative lobes of the PHEX protein, suggesting these are functionally important regions of the molecule. Circulating levels of intact FGF23 were significantly elevated (median level 101.9 pg/mL; reference range 16.1-42.2 pg/mL). No significant sex differences, as well as no phenotypic differences were identified between patients with putative truncating and non-truncating PHEX mutations. However, patients with N-terminal PHEX mutations had an earlier age of onset of disease (P = 0.015) and higher iFGF23 levels (P = 0.045) as compared to those with C-terminal mutations. These data provide a comprehensive characterization of the largest cohort of patients with XLH reported to date from China, which will help in evaluating the applicability of emerging therapies for this disease in this ethnic group.

Sex-related risks of recurrence of atrial fibrillation after ablation: Insights from the Guangzhou Atrial Fibrillation Ablation Registry

Female sex has been linked with worse prognosis in patients with atrial fibrillation (AF). Clinical risk stratification of women with AF may help decision-making before catheter ablation (CA). To evaluate arrhythmia outcomes and the predictive value of clinical scores for arrhythmia recurrence in a large cohort of Chinese patients with AF undergoing CA. A total 1410 of patients (68.1% men) who underwent AF ablation with scheduled follow-up were analysed retrospectively. Baseline characteristics and ablation outcome were compared between men and women. The predictive values of risk scoring systems for AF recurrence were assessed in women. Recurrence, early recurrence and complications after CA were similar in women and men over similar follow-up periods (20.7±8.0 vs 20.7±9.1 months; P>0.05). Compared with men, women with AF recurrence were older and had a larger left atrial diameter (LAD), less paroxysmal AF, lower left ventricular ejection fraction, lower estimated glomerular filtration rate (eGFR) and higher serum concentrations of B-type natriuretic peptide (BNP) and C-reactive protein (CRP) (all P<0.01). Multivariable analysis showed that age, non-paroxysmal AF, body mass index, coronary artery disease, LAD, early recurrence, eGFR, BNP and CRP were independent risk factors with sex differences (all P<0.05) in the whole cohort. In women, only non-paroxysmal AF, early recurrence, BNP, CRP (all P<0.01) and history of stroke/transient ischaemic attack (P=0.016) were independent risk factors. Of the clinical scoring systems tested, MB-LATER, APPLE, CAAP-AF and BASE-AF2 scores (C-indexes 0.73, 0.72, 0.68 and 0.72, respectively; all P<0.01) had a modest predictive value for AF recurrence after CA in women. CA for AF has similar recurrence risks in women and men, but there are sex differences in the clinical characteristics and risk factors associated with AF recurrence.

Genotype-phenotype relationship in a large cohort of osteogenesis imperfecta patients with COL1A1 mutations revealed by a new scoring system.

Background:Osteogenesis imperfecta (OI), a heritable bone fragility disorder, is mainly caused by mutations in COL1A1 gene encoding α1 chain of type I collagen. This study aimed to investigate the COL1A1 mutation spectrum and quantitatively assess the genotype-phenotype relationship in a large cohort of Chinese patients with OI.Methods:A total of 161 patients who were diagnosed as OI in Department of Endocrinology of Peking Union Medical College Hospital from January 2010 to December 2017 were included in the study. The COL1A1 mutation spectrum was identified by next generation sequencing and confirmed by Sanger sequencing. A new clinical scoring system was developed to quantitatively assess the clinical severity of OI and the genotype-phenotype relationship was analyzed. The independent sample t-test, analysis of variance, Mann-Whitney U-test, Chi-squared test, Pearson correlation, and multiple linear regression were applied for statistical analyses.Results:Among 161 patients with OI, 32.9% missense mutations, 16.8% non-sense mutations, 24.2% splice-site mutations, 24.8% frameshift mutations, and 1.2% whole-gene deletions were identified, of which 38 variations were novel. These mutations led to 53 patients carrying qualitative defects and 67 patients carrying quantitative defects in type I collagen. Compared to patients with quantitative mutations, patients with qualitative mutations had lower alkaline phosphatase level (296 [132, 346] U/L vs. 218 [136, 284] U/L, P = 0.009) and higher clinical score (12.2 ± 5.3 vs. 7.4 ± 2.4, P < 0.001), denoting more severe phenotypes including shorter stature, lower bone mineral density, higher fracture frequency, more bone deformity, vertebral compressive fractures, limited movement, and dentinogenesis imperfecta (DI). Patients would not present with DI if the glycine substitutions happened before the 79th amino acid in triple helix of α1 chains.Conclusions:This presented distinctive COL1A1 mutation spectrum in a large cohort of Chinese patients with OI. This new quantitative analysis of genotype-phenotype correlation would be helpful to predict the prognosis of OI and genetic counseling.

Validation of the preoperative controlling nutritional status score as an independent predictor in a large Chinese cohort of patients with upper tract urothelial carcinoma.

BackgroundPretreatment controlling nutritional status (CONUT) score is a novel index which was used to predict outcomes in cancer patients. We aim to explore the prognostic significance of CONUT score in patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU).Patients and methodsA total of 662 UTUC patients between 2004 and 2016 were retrospectively analyzed. Patients were categorized into three groups based on CONUT score (Normal: 0‐1; Light: 2‐4; Moderate/severe: 5‐12). Associations of CONUT score with oncological outcomes were analyzed using Logistic and Cox regression analysis. Harrell concordance index was used to assess the predictive accuracy of the multivariate models. Subgroup analyses were conducted according to tumor grade and stage.ResultsThe median follow‐up duration was 41 months. Multivariate Logistic analysis showed that high CONUT score was independently associated with high‐grade disease, high pT stage, lymphovascular invasion, sessile carcinoma, variant histology, and positive surgical margins (each P < 0.05). Multivariate analysis demonstrated that CONUT score 5‐12 was an independent factor for worse cancer‐specific survival (CSS, hazard ratio [HR]:2.39, 95% confidence interval [CI] 1.55‐3.68, P < 0.0001), disease recurrence‐free‐survival (RFS, HR: 1.80, 95% CI 1.24‐2.60, P = 0.002), and overall survival (OS, HR: 2.26, 95% CI 1.53‐3.34, P < 0.0001). The estimated c‐index of the multivariate models for CSS, RFS, and OS increased from 0.755, 0.715 and 0.745 to 0.772, 0.723, and 0.756 when CONUT score supplemented. Subgroup analyses showed that especially in patients with high‐grade carcinoma and advanced stage (≥pT3), higher CONUT score predicts decreased CSS, RFS, and OS (all P < 0.05).ConclusionPreoperative CONUT score is a negative independent prognostic indicator for both pathologic and survival outcomes in UTUC, especially in those with high‐grade carcinoma and advanced stage. Adding this parameter into our clinical prediction model is appropriate so as to improve its predictive accuracy.

Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer.

Multigene panel testing of breast cancer predisposition genes have been extensively conducted in Europe and America, which is relatively rare in Asia however. In this study, we assessed the frequency of germline mutations in 40 cancer predisposition genes, including BRCA1 and BRCA2, among a large cohort of Chinese patients with high hereditary risk of BC. From 2015 to 2016, consecutive BC patients from 26 centers of China with high hereditary risk were recruited (n = 937). Clinical information was collected and next-generation sequencing (NGS) was performed using blood samples of participants to identify germline mutations. In total, we acquired 223 patients with putative germline mutations, including 159 in BRCA1/2, 61 in 15 other BC susceptibility genes and 3 in both BRCA1/2 and non-BRCA1/2 gene. Major mutant non-BRCA1/2 genes were TP53 (n = 18), PALB2 (n = 11), CHEK2 (n = 6), ATM (n = 6) and BARD1 (n = 5). No factors predicted pathologic mutations in non-BRCA1/2 genes when treated as a whole. TP53 mutations were associated with HER-2 positive BC and younger age at diagnosis; and CHEK2 and PALB2 mutations were enriched in patients with luminal BC. Among high hereditary risk Chinese BC patients, 23.8% contained germline mutations, including 6.8% in non-BRCA1/2 genes. TP53 and PALB2 had a relatively high mutation rate (1.9 and 1.2%). Although no factors predicted for detrimental mutations in non-BRCA1/2 genes, some clinical features were associated with mutations of several particular genes.

Screening of HNF1A and HNF4A mutation and clinical phenotype analysis in a large cohort of Chinese patients with maturity-onset diabetes of the young

The study aimed to screen the HNF1A and HNF4A mutation in a large Chinese cohort of high clinical suspicion of maturity-onset diabetes of the young (MODY) patients and characterize the clinical features of those patients. The performance of hsCRP as a biomarker to differentiate MODY3 from early onset T2DM was also evaluated. A total of 74 patients with a strong clinical suspicion of MODY from 59 families and 33 newly diagnosed early-onset T2DM were included. HNF1A and HNF4A mutations were analyzed by Sanger sequencing. ROC curves were used to identify the optimal cutoff of hsCRP. One novel (c.864_865insG) and six recurrent HNF1A mutations (R203H, R263H, P379T, L422P, P519L and c.873delC) in 17 patients from 8 families (13.6%), as well as one novel HNF4A (R331H) mutation were identified. Nonspecific clinical presentations were observed in MODYX compared to MODY3 patients. MODY3 subjects exhibited with younger, lower BMI, TG, fasting and postprandial C-peptide, higher HDL than T2DM. Particularly, we confirmed serum hsCRP was lower in MODY3 than T2DM. ROC curve showed a good discrimination with an AUC of 0.852 and identified a cutoff hsCRP of 0.79 (75% sensitivity and 83% specificity). Good glycemic control was observed in all identified patients after switching to glimepiride therapy. The prevalence of HNF1A mutation was relatively lower in Mainland China and HNF4A mutation was rare. Serum hsCRP concentrations performed well in discriminating MODY3 from T2DM. Molecular diagnosis of MODY3/1 did transform management in clinical practice and facilitated the glycemic control.

Lumbar Vertebrae Morphological Analysis and an Additional Approach for Vertebrae Identification in Lumbar Spine DXA Images

Introduction: Bone mineral density measured by dual-energy X-ray absorptiometry (DXA) is the gold standard for diagnosis of osteoporosis. However, DXA interpretation can be influenced by analytic errors which can, in turn, interfere with diagnostic accuracy. One such source of potential error is the accurate identification of specific lumbar vertebrae on lumbar spine DXA images. Although the International Society for Clinical Densitometry has introduced several approaches to aid with this process, there remain individuals whose lumbar vertebrae cannot be labeled with certainty using these approaches. We designed the present study to systematically evaluate lumbar spine DXA images among a large cohort of Chinese patients and present an additional simple strategy for identifying L5 named the “em dash”-shaped L5 or “—”-shaped L5, based upon the two-dimensional relationship between the bilateral pedicles with the central spinous process on DXA images. Methodology: Lumbar spine posteroanterior DXA images from adult patients receiving care at a large tertiary hospital in Beijing, China from May to August 2016 were retrospectively reviewed. For each patient, data were collected regarding key anatomic features seen on DXA (positions of the most superior portions of the iliac crests, the lowest vertebra with ribs, and the longest transverse processes) and the proportion of patients presenting with “H”-shaped L4 and “—”-shaped L5. Chi-squared analyses were used to compare proportions across age strata. Results: DXA images from 1125 patients (79.6% female) were evaluated. The mean age of patients was 52.5 ± 14.8 yr (range: 19–90 yr). A horizontal line drawn across the superior-most portions of the iliac crests crossed the disk space between L4 and L5 among 78.3% of patients. The lowest ribs were most frequently (83.9%) observed at T12. Almost 80% of individuals had the longest transverse processes at L3. L4 was predominantly “H”-shaped (73.3%), however we found that the proportion of individuals with “H”-shaped L4 decreased steadily after 50 yr of age (p < 0.001). By contrast we observed that L5 was predominantly “—”-shaped (80.3%), with no significant differences in proportions across all age strata (p = 0.063). Conclusions: The “—”-shaped L5 can be incorporated as an additional reference tool for lumbar spine DXA image analysis and may be particularly helpful for lumbar vertebrae identification among patients over 50 yr of age.

GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation

Mutations in the Krüppel-like zinc finger transcription factor GLI-similar 3 (GLIS3) have first been associated with a syndrome combining two rare genetic endocrine diseases, namely neonatal diabetes and congenital hypothyroidism (OMIM #610199)1. Since then, 12 patients have been reported so far with a broad spectrum of a multi-organ disease including growth delay, renal cystic dysplasia, liver fibrosis, congenital glaucoma and osteopenia, besides neonatal diabetes and congenital hypothyroidism. In a large cohort of Chinese patients with congenital hypothyroidism without further multi-organ disease, the prevalence of GLIS3 mutations was 0.3%2. The role of GLIS3 has been extensively described for beta cell differentiation. However, the role of GLIS3 for thyroid follicular cell differentiation and function remained unknown.