Large Cohort Of Chinese Patients Research Articles

Comprehensive genetic analysis uncovers the mutational spectrum of MFRP and its genotype-phenotype correlation in a large cohort of Chinese microphthalmia patients

PurposeMicrophthalmia is a severe congenital ocular disease featured by abnormal ocular development. The aim of this study was to detail the genetic and clinical characteristics of a large cohort of Chinese patients with microphthalmia related to MFRP variants, focusing on uncovering genotype-phenotype correlations. MethodsFifty microphthalmia patients from 44 unrelated Chinese families were recruited. Whole-exome sequencing (WES) was conducted to analyze the coding regions and adjacent intronic regions of MFRP. Axial lengths (AL) were measured for all probands and available family members. Protein structures of mutations with high frequency in our cohort were predicted. The genotype-phenotype correlations were explored by statistical analysis. ResultsSixteen MFRP variants were detected in 17 families, accounting for 38.64 % of all microphthalmia families. There were 9 novel mutations (c.427+1G>C, c.428-2A>C, c.561_575del:p.A188_E192del, c.836G>A:p.C279Y, c.1010_1021del:p.H337_E340del:p.Y479*, c.1516_1517del:p.S506Pfs*66, c.1561T>G:p.C521G, c.1616G>A:p.R539H, and c.1735C>T:p.P579S) and six previously reported variants in MFRP, with p.E496K and p.H337_E340del being highly frequent, found in eight (47.06 %) and two families (11.76 %), respectively. Seven variants (43.75 %) were located in the C-terminal cysteine-rich frizzled-related domain (CRD) (7/16, 43.75 %). Protein prediction implicated p.E496K and p.H337_E340del mutations might lead to a destabilization of the MFRP protein. The average AL of all 42 eyes was 16.02 ± 1.05 mm, and 78.36 % of eyes with AL < 16 mm harbored p.E496K variant. Twenty-six eyes with variant variant had shorter AL than that of the other 16 eyes without this variant (p = 0.006), highlighting a novel genotype-phenotype correlation. ConclusionsIn this largest cohort of Chinese patients with microphthalmia, the 9 novel variants, high frequency of p.E496W, and mutation hotspots in CRD reveals unique insights into the MFRP mutation spectrum among Chinese patients, indicating ethnic variability. A new genotype-phenotype correlation that p.E496K variant associated with a shorter AL is unveiled. Our findings enhance the current knowledge of MFRP-associated microphthalmia and provide valuable information for prenatal diagnosis as well as future therapy.

Comprehensive analysis of TMB, TNB, and HLA via NGS sequencing in a large cohort of Chinese pan-cancer patients.

2656 Background: Evidence suggests that patients with high tumor mutational burden (TMB) and tumor neoantigen burden (TNB) are more likely to benefit from Immune checkpoint inhibitors (ICIs). Furthermore, loss of heterozygosity (LOH) in human leukocyte antigen (HLA) alleles, particularly HLA class I, impairs neoantigen presentation and contributes to resistance against ICIs. This study provides real-world insights into the distribution of TMB, TNB, and HLA variations within a large cohort of Chinese patients with various cancers. Methods: From 2021 to 2023, we performed a retrospective analysis on 1603 cancer patients, examining genetic mutations and HLA traits using the Med1 CDx DNA-based NGS panel targeting 601 cancer-related genes and HLA class I. TMB was calculated as the average number of coding mutations per megabase of the genome. HLA class I alleles (HLA-A, B and C) were identified and predicted using the OptiType and pVACtools software suites. TNB was defined as the number of high-affinity (IC50 ≤ 50 nM) neoantigens per megabase of the genome. Statistical analyses were performed to explore the relationship between TMB, TNB, and LOH status in critical regions of HLA. Results: This study enrolled participants across 25 cancer types. With 32.56% having non-small cell lung cancer (NSCLC), 11.79% colorectal carcinoma (CRC), and 18.34% unidentified solid tumors. The remaining 37.31% comprised cases of cholangiocarcinoma, hepatocellular carcinoma, pancreatic cancer, etc. High-affinity neoantigen-generating genes such as TP53, EGFR, KRAS, LRP1B, DMD, and FAT1 were identified. Our findings indicate substantial variation in tumor neoantigen burden (TNB) across various cancer types and even among different samples within the same type. Neuroendocrine tumors exhibited the highest TNB at 4 neoantigens/Mb, followed by esophageal cancer (3.3), melanoma and urothelial carcinoma (2.67 each), indicating higher TNB levels in these cancers compared to others. A significant positive correlation was observed between TMB and TNB (p&lt; 0.0001). Analysis revealed no significant TNB differences attributable to age (cutoff at 60 years) or gender. However, individuals aged over 70 years demonstrated a higher TNB of 4 compared to those under 70 with 3.33, highlighting potential age-related differences in TNB. Conclusions: Our analysis highlights significant variation in TNB across cancer types, with the highest TNB found in neuroendocrine tumors and the lowest in gastrointestinal stromal tumors, indicating TNB's value as a biomarker for optimizing ICI therapy. Furthermore, we found that people over 70 years old have higher TNB levels than younger individuals, suggesting a potential for improved ICI efficacy without chemotherapy. The evident strong correlation between Tumor Mutational Burden (TMB) and TNB underlines their crucial role in the success of cancer immunotherapy.

The pan-cancer landscape of SMARCA4 and SMARCB1 alterations in a large cohort of Chinese patients.

e14636 Background: Alterations of SMARCA4 or SMARCB1 (SMARCA4/B1) proteins have been identified in various aggressive cancers. Recent studies show that tumors harboring deleterious SMARCA4/B1 alterations express PD-L1 and respond to immune checkpoint inhibitor (ICI) therapies. Current ongoing immunotherapy-based clinical trials for cancers deficient in SMARCA4/B1 include combinations of atezolizumab and the TIGIT antibody tiragolumab (Phase II), as well as nivolumab and the CTLA-4 antibody ipilimumab (Phases II &amp; III). Here we present a comprehensive analysis of the pan-cancer landscape of SMARCA4/B1 alterations, based on real-world data from a large cohort of Chinese patients. Methods: From 2021 to 2023, we collected genomic information from 16,113 cancer patients, spanning more than 40 different cancer types. These patients had undergone targeted next-generation sequencing (NGS) through the Med1CDx panel, which targets 601 cancer-associated genes. After excluding 1,034 samples of unidentified tumor origins, 15,079 samples were analyzed further. The analysis included somatic and germline pathogenic/likely pathogenic (P/LP) single-nucleotide variants, insertions/deletions, and copy number alteration in SMARCA4/B1. Results: We identified 421/15079 (2.8%) patients with SMARCA4/B1 alterations, with a median age of 63 years (range 13-90). Cancer types with a higher frequency of SMARCA4/CB1 mutations include: endometrial cancer (9.8%), thyroid cancer (6.9%), gastric cancer (6.2%), cholangiocarcinoma (5.7%), and lung cancer (4.4%). The predominant mutation type is variants of uncertain significance (VUS) gene mutations, constituting 72% (302/421) of the spectrum, with nearly all being missense mutations. These are mainly observed in lung cancer, thyroid cancer, and colorectal cancer. The frequency of pathogenic/likely pathogenic mutations is 28% (119/421), mainly distributed in lung cancer and liver cancer. Q201L, P222L, and E1364del are the most common mutations in SMARCA4, with a mutation rate of approximately 4.1%, occurring across over five cancer types. The most common co-mutations of SMARCA4/B1 were TP53 (47.3%), EGFR (25.4%), KRAS (15.9%), STK11 (7.1%) and CDKN2A (7.4%). Clinicopathological feature of age showed no significant differences between SMARCA4/B1 mutant and wild-type groups. Tissues with SMARCA4/B1 mutations exhibited a higher tumor mutational burden (TMB) (median=8.3) than wild-type tissues (median=4.2) (P &lt; 0.001). Conclusions: Elevated TMB levels in patients with SMARCA4/B1 mutations suggest a significant potential benefit from immunotherapy. The presence of co-mutations may also aid in predicting the efficacy of combination immunotherapy treatments. Furthermore, the high prevalence of VUS emphasizes the need for additional research to determine their clinical relevance.

Association of chr11q13 amplification with survival and recurrence in patients with surgically treated hepatocellular carcinoma.

e16253 Background: Hepatocellular carcinoma (HCC) is a highly lethal and aggressive malignant tumor characterized by high rates of recurrence and metastasis, and low survival outcomes. The current treatments available for HCC have shown limited success, and the prevalence of genomic characterization and their association with survival and recurrence in HCC patients are largely unknown. Methods: The investigation enrolled 1,221 Chinese individuals diagnosed with primary HCC. This study collected samples including tumor and paired tumor-free tissues and clinical characteristics. Among them, 348 patients' clinical outcome data, including overall survival (OS) and recurrence-free survival (RFS) were gathered. Genomic analysis was conducted through panel sequencing by OrigiMed. Hazard ratios were calculated employing both univariate and multivariate Cox proportional hazards regression models. The log-rank test and Kaplan-Meier plots were used to assess comparison of clinical outcomes by various prognostic factors. For other statistical analyses, a two-tailed unpaired t-test and Fisher's exact test were applied. Results: With a median age of 54, 87% of the cases were male. Pertaining to risk factors, 74% cases had HBV infection and 62% cases were cirrhosis. Meanwhile, serum AFP levels greater (or less) than 400 ng/mL were present in 299 cases (or 485 cases). Panel sequencing identified the most prevalent mutations ( &gt; 10%, excluding copy number variations) in TP53 (60%), TERT (40%), CTNNB1 (21%), AXIN1 (14%), LRP1B (14%), ARID1A (13%), RB1 (12%) and TSC2 (11%). The most frequently amplified genes were located at chr11q13, including CCND1 (9%), FGF19 (9%), FGF4 (7%) and FGF3 (7%). Survival analysis indicated that patients with Chr11q13 amp had significantly shorter OS and RFS. Further studies revealed a higher incidence of Chr11q13 amp in patients at advanced stages III/IV (64/564, 11%) compared to early-stage I/II (38/523, 7%), and in patients with vascular invasion (31/220, 14%) versus those without (44/599, 7%). No significant differences were observed in tumor mutational burden and HLA-I evolutionary divergence between patients with various Chr11q13 amp statuses. Furthermore, multivariate Cox proportional hazards regression models were utilized to examine the relationship between Chr11q13 amp status, characteristics and outcomes. Among the 248 patients with comprehensive clinical characteristics and available OS and RFS data, analyses indicated significant negative correlations between Chr11q13 amp and embolus with both OS and RFS. Conclusions: Our study elucidates that the presence of Chr11q13 amp was significantly associated with worse survival and increased risk of recurrence among a large cohort of Chinese patients with HCC. This discovery yields important insights into the understanding of HCC and has the potential to benefit personalized therapy.

Investigation of RBM10 mutation and its associations with clinical and molecular characteristics in EGFR-mutant and EGFR-wildtype lung adenocarcinoma

BackgroundRBM10 is commonly mutated in lung adenocarcinoma (LUAD). However, its role in the pathogenesis of LUAD remains undefined. EGFR-mutant LUAD represents a distinct subset of non-small cell lung cancer (NSCLC). The function of RBM10 in tumor pathogenesis is supposed to differ between EGFR-mutant and EGFR-wt LUAD. This study aimed to interrogate the prevalence of RBM10 mutation in a large cohort of Chinese patients with LUAD and investigate the association of RBM10 mutation with clinical and molecular characteristics of EGFR-mutant and EGFR-wt LUAD. MethodsTumor sequencing data from 2848 Chinese patients with LUAD were retrospectively reviewed and analyzed. The prevalence of RBM10 was also compared with other three cohorts: OrigMed (n = 1222), MSKCC (n = 1267), and TCGA (n = 566). The associations of RBM10 mutation with clinical and molecular characteristics were assessed. An external cohort of 182 patients with LUAD who received PD-1 inhibitor were used to investigate the association of RBM10 mutation with clinical outcomes upon immunotherapy. ResultsOur cohort showed a higher prevalence of RBM10 in EGFR-mutant LUAD than in EGFR-wt LUAD (14.8 % vs. 6.5 %, p < 0.001). The enrichment of RBM10 mutations in EGFR-mutant LUAD was also seen in another Chinese cohort (OrigMed: 14.9 % vs. 7.8 %, p < 0.001), but not in the two western cohorts (MSKCC: 7.4 % vs. 9.5 %, p = 0.272; TCGA: 8.1 % vs. 6.7 %, p = 0.624). RBM10 mutations co-occurred more frequently with EGFR L858R mutations (23.7 %) than with other types of EGFR mutations (19 del: 7.7 %; other: 7.1 % in others, p < 0.001). In EGFR-mutant LUAD, RBM10 mutations were more commonly found in stage I (18.2 %) and II (21.8 %) vs. stage III (9.4 %) and IV (11.3 %) tumors (p < 0.001). The proportion of PD-L1 positive expression in EGFR-mutant LUAD with concomitant RBM10 mutation was not different from that those without RBM10 mutations (41.8 % vs. 47.9 %, p = 0.566). In contrast, RBM10 mutation occurred more frequently in EGFR-wt LUAD at stage II-IV (stage II: 12.0 %, stage III: 8.7 %, stage IV: 6.6 %) than at stage I (2.8 %). EGFR-wt LUAD with concomitant RBM10 mutations had higher proportions of PD-L1 expression positivity (78.9 % vs. 61.9 %, p = 0.014) and higher tumor mutational load (8.97 vs. 2.99 muts/Mb, p < 0.001) than those without. Patients with EGFR-wt LUAD who also harbored RBM10 loss of function (LOF) mutations had a longer median PFS upon immunotherapy than those with RBM10 non-LOF mutations (7.15 m vs. 2.60 m, HR = 4.83 [1.30–17.94], p = 0.010). ConclusionWe comprehensively investigated RBM10 mutations in a Chinese cohort with LUAD. Compared to western cohorts, a significant enrichment of RBM10 mutations in EGFR-mutant LUAD compared to EGFR-wildtype LUAD in the Chinese population. RBM10 mutation shows different associations with clinical and molecular characteristics between EGFR-mutant and EGFR-wt LUAD, suggesting a divergent mechanism between these two subsets via which RBM10 deficiency contribute to tumor pathogenesis. The findings contribute to our understanding of the molecular landscape of LUAD and highlight the importance of considering population-specific factors in cancer genomics research.

Non-motor symptoms in patients with isolated dystonia: comparison between the age of onset

Background: The etiology and motor presentation differs between pediatric- and adult-onset dystonia. Emerging evidence has demonstrated that non-motor symptoms are frequent in adult dystonia, which affect the quality of life. By contrast, little is known about the frequency and severity of such presentations in pediatric-onset individuals. Here, we investigated the motor and non-motor symptoms in a large cohort of Chinese patients with isolated dystonia and compared between pediatric-onset and adult-onset groups.Methods: In this retrospective study, 34 pediatric-onset patients and 197 adult-onset patients with isolated dystonia were recruited. Motor impairment was assessed by the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). Non-motor symptoms were evaluated through several validated scales, including fatigue (by Fatigue Severity Scale, FSS), excessive daytime sleepiness (by Epworth Sleepiness Scale, ESS), sleep disturbance (by Pittsburgh Sleep Quality Index, PSQI), anxiety (by Beck Anxiety Inventory, BAI) and depression (by Beck Depression Inventory 21, BDI-21).Results: Generalized dystonia was more common in pediatric-onset patients and focal dystonia was more common in adult-onset patients (p &amp;lt; 0.001). Generally, the BFMDRS score in total pediatric-onset group was higher than adult-onset group (p = 0.002). No differences was found in BFMDRS score between pediatric-onset and adult-onset patients with cervical and multifocal subtype dystonia. Compared with adult-onset group, pediatric-onset group had a lower rate of sleep disturbance (p &amp;lt; 0.0001) and similar rates of fatigue, excessive daytime sleepiness, depression and anxiety. Logistic regression analysis on patients with cervical dystonia indicated that the adult-onset and motor severity were independently associated with increased odds of sleep disturbance (p = 0.03) and depression (p = 0.01), respectively.Conclusion: Pediatric-onset dystonia patients were less likely to display focal dystonia. Most non-motor symptoms in pediatric-onset patients were comparable to their adult-onset counterparts. Non-motor presentations may to some extent correlate with motor symptoms, but their underlying pathophysiology need to be investigated further.

Comprehensive genetic analysis reveals the mutational landscape of ABCA4-associated retinal dystrophy in a Chinese cohort

PurposeTo depict the variant profiles of the ABCA4 gene in a large Chinese cohort of patients with ABCA4-associated retinal dystrophy (ABCA4-RD). MethodsWe recruited 290 unrelated Chinese patients with ABCA4-RD and did ABCA4 mutational screening by a combination of Sanger sequencing, targeted exome sequencing, entire ABCA4 locus sequencing, and whole genome sequencing (WGS). The pathogenicity of variants was assessed using in silico tools or in vitro splicing assays following the American College of Medical Genetics and Genomics guidelines. ResultsTwo hundred sixty-eight distinct pathogenic variants were identified, and 57 were novel. In 580 alleles, 22 noncoding region variants outside canonical splice sites and 4 structural variations were found in 44 alleles accounting for 7.6% of all alleles. Bioinformatics analysis showed the complex mechanism of aberrant splicing productsnatural splice site disruption, branch point destruction, and cryptic splice site activation. Correspondingly, minigene assays validated the various abnormal splicing products, including exon skipping, exon elongation, partial exon deletion, and pseudoexon insertion. WGS identified the first inversion variation in ABCA4. ConclusionsThis study systematically depicted the variant profiles of ABCA4 and revealed the missing alleles of patients with ABCA4-RD in a large Chinese cohort. Our findings demonstrated the complexity of molecular diagnosis of Mendelian diseases and the efficiency of WGS for detecting structural variants.

Mutational spectrum and clinical features of GBA1 variants in a Chinese cohort with Parkinson’s disease

GBA1 variants are important risk factors for Parkinson’s disease (PD). Most studies assessing GBA1-related PD risk have been performed in European-derived populations. Although the coding region of the GBA1 gene in the Chinese population has been analyzed, the sample sizes were not adequate. In this study, we aimed to investigate GBA1 variants in a large Chinese cohort of patients with PD and healthy control and explore the associated clinical characteristics. GBA1 variants in 4034 patients and 2931 control participants were investigated using whole-exome and whole-genome sequencing. The clinical features of patients were evaluated using several scales. Regression analysis, chi-square, and Fisher exact tests were used to analyze GBA1 variants and the clinical symptoms of different groups. We identified 104 variants, including 8 novel variants, expanding the spectrum of GBA1 variants. The frequency of GBA1 variants in patients with PD was 7.46%, higher than that in the control (1.81%) (P < 0.001, odds ratio [OR] = 4.38, 95% confidence interval [CI]: 3.26–5.89). Among patients, 176 (4.36%) had severe variants, 34 (0.84%) carried mild variants, three (0.07%) had risk variants, and 88 (2.18%) carried unknown variants. Our study, for the first time, found that p.G241R (P = 0.007, OR = 15.3, 95% CI: 1.25–261.1) and p.S310G (P = 0.005, OR = 4.86, 95% CI: 1.52–28.04) variants increased the risk of PD. Patients with GBA1 variants exhibited an earlier onset age and higher risk of probable rapid-eye-movement sleep behavior disorder, olfactory dysfunction, depression, and autonomic dysfunction than patients without GBA1 variants.

Clinical and genetic characterization of a large cohort of Chinese patients with Bietti crystalline retinopathy.

To investigate the clinical and genetic characteristics for a large cohort of Chinese patients with Bietti crystalline retinopathy (BCR). A total of 208 Chinese BCR patients from 175 families were recruited. Comprehensive clinical evaluations and genetic analysis were performed. Genotype-phenotype correlations were evaluated through statistical analysis. The patients' median age was 37 years (range, 20-76 years). The median best corrected visual acuity (BCVA) was 0.8 LogMAR unit (range, 2.8 to -0.12). A significant decline of BCVA was revealed in patients over 40 years old (P<0.001). Two clinical types were observed: peripheral type (type P) and central type (type C). Significantly more type C patients had a worse central visual acuity, but a more preserved retinal function (P<0.05). Molecular screening detected biallelic CYP4V2 pathogenic variants in 98.3% (172/175) of the families, including 19 novel ones. The most frequent pathogenic variant was c.802-8_810del17insGC, with the allele frequency of 55.7% (195/350), followed by c.992A>C (28/350, 8%) and c.1091-2A>G (23/350, 6.6%). BCR patients with one c.802-8_810del17insGC and one truncating variant (IVS6-8/Tru) had BCVA>1.3 LogMAR unit (Snellen equivalent<20/400) at a younger age than those with homozygous c.802-8_810del17insGC variants (homo IVS6-8) (P=0.031). BCR patients preserved relatively good vision before 40 years old. Two distinct clinical types of BCR were observed. BCR patients with IVS6-8/Tru had an earlier decline in visual acuity than those with homo IVS6-8. Our findings enhance the knowledge of BCR and will be helpful in patient selection for gene therapy.

Clinical and mutational spectrum of paediatric Charcot-Marie-Tooth disease in a large cohort of Chinese patients.

Background: Charcot-Marie-Tooth disease (CMT) is the most common inherited neurological disorder suffered in childhood. To date, the disease features have not been extensively characterized in the Chinese paediatric population. In this study, we aimed to analyse the clinical profiles and genetic distributions of a paediatric CMT cohort in China. Methods: A total of 181 paediatric CMT patients were enrolled. After preexcluding PMP22 duplication/deletion by multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing, targeted next-generation sequencing (NGS) or whole-exome sequencing (WES) was performed to obtain a genetic diagnosis. Detailed information was collected to explore the spectrum of subtypes and genotype-phenotype correlations. Results: Pathogenic mutations were identified in 68% of patients in this study; with PMP22 duplication, MFN2 and GJB1 were the most frequent disease-causing genes. Of note, respect to the higher prevalence worldwide, CMT1A (18.2%) was relatively lower in our cohort. Besides, the mean age at onset (8.3 ± 5.7years) was significantly older in our series. In genotype-phenotype analyse, PMP22 point mutations were considered the most severe genotypes and were mostly de novo. In addition, the de novo mutations were identified in up to 12.7% of all patients, which was higher than that in other studies. Conclusion: We identified a relatively lower detection rate of PMP22 duplication and a higher frequency of de novo variants among paediatric patients in China. We also identified the genetic and phenotypic heterogeneity of this cohort, which may provide clues for clinicians in directing genetic testing strategies for Chinese patients with early-onset CMT.

Vogt-Koyanagi-Harada disease in pediatric, adult and elderly: clinical characteristics and visual outcomes.

To depict a whole spectrum of clinical feartures and visual prognosis among pediatric, adult, and elderly Vogt-Koyanagi-Harada disease (VKH) patients. Retrospective chart review was conducted in 2571 VKH patients diagnosed from April 2008 to January 2022. Based on age of disease onset, patients were divided into pediatric (age ≤ 16years), adult (16 < age < 65years), and elderly (age ≥ 65years) VKH group. Ocular and extraocular manifestations were compared among these patients. Visual outcomes and complications were evaluated using logistic regression models and restricted cubic splines analysis. The median follow-up time was 48 (IQR, 12-60) months. Pediatric, adult and elderly VKH were found in 106 (4.1%), 2355 (91.6%), and 110 (4.3%) patients, respectively. All of the patients showed similar ocular manifestations in the context of disease phasing. The proportion of neurological and auditory manifestations in pediatric (42.3% and 7.5%) VKH patients was significantly lower than that in adults (66.5% and 47.9%) and elderly (68.2% and 50%) (both p < 0.0001). An increased risk of macular abnormalities was seen in adults (OR, 3.43; 95% CI, 1.62-7.29) compared with elderly VKH. An inverted-U-shaped pattern was observed between disease onset age and a poor visual outcome (visual acuity 6/18 or worse) according to OR value in VKH patients. The highest risk of BCVA ≤ 6/18 was observed in 32years at disease onset (OR, 1.51; 95% CI, 1.18-1.94). A higher risk of visual loss was observed in adult VKH patients (OR, 9.06; 95% CI, 2.18-37.6) compared with elderly VKH patients. And stratified by macular abnormalities, the interaction test was not significant (P = 0.634). Our study identified, for the first time, a whole spectrum of clinical features of VKH based on a large cohort of Chinese patients. Adult VKH patients have an increased risk of poor visual outcomes, possibly due to increased frequency of macular abnormalities.

Clinical Characteristics, Treatment Patterns, and Effectiveness in Chinese Patients with Angina Pectoris Using Electronic Patient-Reported Outcomes: Protocol for a Multicenter, Prospective, Cohort Study (GREAT).

Angina pectoris (AP) is the initial and the most common manifestation of coronary artery disease (CAD). Therefore, management and control of AP can help prevent further complications associated with CAD. However, there is under-reporting of angina symptoms in clinical practice, resulting in under-treatment and reduced quality of life (QoL). Prospective and standardized monitoring is needed to support timely and appropriate treatment. To establish a large cohort of Chinese patients with AP and compare the effectiveness of different anti-angina regimens with the help of electronic patient-reported outcomes (e-PROs), using the Seattle Angina Questionnaire (SAQ) to assess health status. The registry study (GREAT) is a multicenter, prospective, observational, cohort study. Patients diagnosed with AP will be enrolled from 10 hospitals and assessed based on the different anti-anginal regimens. Patients will be followed up every 3months from baseline to 12months to observe the difference in the therapeutic effectiveness of the drugs. Data will be collected in the form of e-PROs combined with on-site visit records. The change in SAQ summary score (SAQ SS) at Month 12 from baseline will be the primary outcome. The secondary measures will include changes in SAQ SS at Months 3, 6, and 9 from baseline, changes in retest results of vascular stenosis imaging at Month 12 from baseline, and medication adherence based on the proportion of days covered. Safety data will be evaluated based on the incidence of adverse events (AEs). This study will evaluate the effectiveness of anti-anginal regimens using ePROs in real-world settings in China. The results from this study may provide a new perspective on treatment patterns and the effectiveness of different anti-anginal regimens for patients with AP. NCT05050773.

Phenotypic and genetic characteristics of 130 patients with mucopolysaccharidosis type II: A single-center retrospective study in China.

Background: Mucopolysaccharidosis Type II (MPS II) is a rare, progressive and ultimately fatal X-linked lysosomal storage disorder caused by mutations in the iduronate-2-sulfatase (IDS) gene. This report conducted a retrospective analysis to investigate the clinical characteristics, genotypes and management strategies in a large cohort of Chinese patients with MPS II. Methods: In this study, we explored 130 Chinese patients with MPS II between September 2008 and April 2022. Clinical manifestations, auxiliary examination, IDS pathogenic gene variants and IDS enzyme activity, surgical history were analysed in the study. Results: A total of 130 patients were enrolled and the mean age at diagnosis was 5years old. This study found the most common symptoms in our patients were claw-like hands, followed by coarse facial features, birthmarks (Mongolian spot), delayed development, inguinal or umbilical hernia. The most commonly cardiac manifestations were valve abnormalities, which were mitral/tricuspid valve regurgitation (71.9%) and aortic/pulmonary valve regurgitation (36.8%). We had found 43 different IDS pathogenic gene variants in 55 patients, included 16 novel variants. The variants were concentrated in exon 9 (20% = 11/55), exon 3 (20% = 11/55) and exon 8 (15% = 8/55). A total of 50 patients (38.5%) underwent surgical treatment, receiving a total of 63 surgeries. The average age of first surgery was 2.6years, and the majority of surgery (85.7%, 54/63) was operated before 4years old. The most common and earliest surgery was hernia repair. Three patients were died of respiratory failure. Conclusion: This study provided additional information on the clinical, cardiac ultrasound and surgical procedure in MPS II patients. Our study expanded the genotype spectrum of MPS II. Based on these data, characterization of MPS II patients group could be used to early diagnosis and treatment of the disease.

Somatic IDH1 Hotspot Variants in Chinese Patients With Pheochromocytomas and Paragangliomas.

IDH1 is a pheochromocytoma/paraganglioma (PPGL) susceptibility gene; however, its role, especially in the Chinese population, has not been characterized. To determine the prevalence of somatic IDH1 hotspot variants in a large cohort of Chinese patients with PPGLs and to summarize associated phenotypes. This retrospective cross-sectional study was based on a main cohort of 1141 patients with PPGLs from 2 tertiary-care centers in China. We included 50 cases with urinary bladder paragangliomas (UBPGLs), of whom 29 were part of the main cohort and 21 were from other centers. Two additional cases with IDH1 hotspot variants not part of the main cohort were also included for summarizing IDH1-associated phenotypes. Next-generation sequencing of tumor DNA was used to analyze a customized panel of genes. The overall prevalence of IDH1 hotspot variants in the main cohort was 0.5% (6/1141). Among those PPGLs without mutations in 15 common driver genes, the prevalence of IDH1 variants was 0.9% (4/455). When restricted to paraganglioma (PGL) without mutations, the prevalence reached 4.7% (4/86). Among UBPGLs, IDH1 hotspot variants accounted for 8% (4/50). Together, all 10 patients (9 PGLs and 1 pheochromocytoma) with IDH1 hotspot variants, including 3 females with concurrent EPAS1 hotspot variants, had apparently sporadic tumors, without metastasis or recurrence. There were 3 patients with biochemical data, all showing a non-adrenergic phenotype. The somatic IDH1 hotspot variants cause PPGL development in some Chinese patients, especially among those apparently sporadic PGLs with a non-adrenergic phenotype and without mutations in major PPGL driver genes.

Hyperparathyroidism in a Large Cohort of Chinese Patients With Tumor-induced Osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. Hyperparathyroidism (HPT) including secondary HPT (SHPT) and tertiary HPT (THPT) in TIO patients, which is believed to be associated with phosphate supplementation, has not been well documented. To clarify the prevalence, clinical characteristics, and risk factors for HPT in a large cohort of Chinese patients with TIO in our hospital. This retrospective study enrolled 202 patients with TIO. Occurrence of HPT in patients with TIO. HPT was observed in 91 patients (91/202, 45.1%): 84 patients (41.6%) with SHPT and 7 patients (3.5%) with THPT. All patients with THPT underwent parathyroidectomy and only 1 patient experienced recurrence. Compared with patients without HPT, patients with SHPT had longer disease duration, higher rate of phosphate and calcitriol supplementation, lower serum calcium, lower urine calcium excretion, and higher urine phosphate excretion. Compared with patients with SHPT, patients with THPT had even longer disease duration and a higher rate of phosphate and calcitriol supplementation. PTH levels showed positive correlation with intact FGF23 and 1,25-dihydroxyvitamin D levels, but not 25-hydroxy vitamin D level in patients with TIO. Multivariate logistic regression analysis showed that long disease duration and phosphate supplementation were independently associated with occurrence of HPT in patients with TIO. Further logistic regression analysis and restricted cubic spline model revealed dose-response relationship between cumulative dose of phosphate supplementation and PTH levels. HPT is common in patients with TIO. To avoid the occurrence of HPT in patients with TIO, timely diagnosis and tumor resection is necessary and an excessive dose of phosphate supplementation is not suggested before surgery.

The optimal diagnostic criteria of endogenous hyperinsulinemic hypoglycemia based on a large cohort of Chinese patients.

An end-of-fast insulin level ≥ 3 µIU/ml, C-peptide level ≥ 0.6 ng/ml, and proinsulin level ≥ 5 pmol/l with end-of-fast glucose level ≤ 3.0 mmol/l have been established as the criteria for endogenous hyperinsulinemic hypoglycemia. However, all these criteria have been proposed based on patients in Western populations. This study aimed to determine the optimal criteria using a large series of Chinese patients. This retrospective study comprised 144 patients with surgically proven insulinoma and 40 controls who underwent a 72-h fasting test at the Peking Union Medical College Hospital(PUMCH) from 2000 to 2020. Receiver operating characteristic curves were used for analysis. In this series of patients, the optimal diagnostic criteria for endogenous hyperinsulinemic hypoglycemia were insulin ≥ 5.5 μIU/ml, C-peptide ≥ 0.7 ng/ml, and proinsulin ≥ 12 pmol/l with end-of-fast glucose ≤ 2.8 mmol/l; the sensitivity and specificity were 99% and 100% for insulin, 100% and 100% for C-peptide, and 93% and 100% for proinsulin, respectively. The diagnostic efficacy of the criteria based on Western populations was then tested. The sensitivity and specificity of end-of-fast insulin ≥ 3 μIU/ml, C-peptide ≥ 0.6 ng/ml, and proinsulin ≥ 5 pmol/l with end-of-fast glucose ≤ 3.0 mmol/l were 100% and 83%, 100% and 80%, and 97% and 78%, respectively. New and optimized diagnostic criteria for endogenous hyperinsulinemic hypoglycemia in Chinese populations have been proposed, and these criteria yield satisfactory accuracy.

ANOS1 variants in a large cohort of Chinese patients with congenital hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare congenital gonadal dysplasia caused by defects in the synthesis, secretion or signal transduction of hypothalamic gonadotropin releasing hormone. The main manifestations of CHH are delayed or lack puberty, low levels of sex hormones and gonadotropins, and may be accompanied with other clinical phenotypes. Some patients with CHH are also accompanied with anosmia or hyposmia, which is called Kalman syndrome (KS). ANOS1, located on X chromosome, is the first gene associated with CHH in an X-linked recessive manner. This study aims to provide a basis for the genetic diagnosis of CHH by analyzing the gene variant spectrum of ANOS1 in CHH and the relationship between clinical phenotype and genotype. In this study, whole exome sequencing (WES) was used to screen rare sequencing variants (RSVs) of ANOS1 in a Chinese cohort of 165 male CHH patients. Four commonly used in silico tools were used to predict the function of the identified RSVs in coding region, including Polyphen2, Mutation Taster, SIFT, and Combined Annotation Dependent Depletion (CADD). Splice Site Prediction by Neural Network (NNSPLICE) was employed to predict possibilities of intronic RSVs to disrupt splicing. American College of Medical Genetics and Genomics (ACMG) guidelines was used to assess the pathogenicity of the detected RSVs. The ANOS1 genetic variant spectrum of CHH patients in Chinese population was established. The relationship between clinical phenotype and genotype was analyzed by collecting detailed clinical data. Through WES analysis for 165 CHH patients, ANOS1 RSVs were detected in 17 of them, with the frequency of 10.3%. A total of 13 RSVs were detected in the 17 probands, including 5 nonsense variants (p.T76X, p.R191X, p.W257X, p.R262X, and p.W589X), 2 splicing site variants (c.318+3A>C, c.1063-1G>C), and 6 missense variants (p.N402S, p.N155D, p.P504L, p.C157R, p.Q635P, and p.V560I). In these 17 CHH probands with ANOS1 RSVs, many were accompanied with other clinical phenotypes. The most common associated phenotype was cryptorchidism (10/17), followed by unilateral renal agenesis (3/17), dental agenesis (3/17), and synkinesia (3/17). Eight RSVs, including p.T76X, p.R191X, p.W257X, p.R262X, p.W589X, c.318+3A>C, c.1063-1G>C, and p.C157R, were predicted to be pathogenic or likely pathogenic ANOS1 RSVs by ACMG. Eight CHH patients with pathogenic or likely pathogenic ANOS1 variants had additional features. In contrast, only one out of nine CHH patients with non-pathogenic (likely benign or uncertain of significance) ANOS1 variants according to ACMG exhibited additional features. And function of the non-pathogenic ANOS1 variants accompanied with other CHH-associated RSVs. The ANOS1 genetic spectrum of CHH patients in Chinese population is established. Some of the correlations between clinical phenotype and genotype are also established. Our study indicates that CHH patients with pathogenic or likely pathogenic ANOS1 RSVs tend to exhibit additional phenotypes. Although non-pathogenic ANOS1 variants only may not be sufficient to cause CHH, they may function together with other CHH-associated RSVs to cause the disease.

Lynch syndrome pre-screening and comprehensive characterization in a multi-center large cohort of Chinese patients with colorectal cancer.

Objective:Lynch syndrome (LS) pre-screening methods remain under-investigated in colorectal cancers (CRCs) in Asia. Here, we aimed to systematically investigate LS pre-screening and comprehensively characterize LS CRCs.Methods:Microsatellite instability (MSI) and germline variants of DNA mismatch repair (MMR) genes were examined in 406 deficient MMR (dMMR) and 250 proficient MMR CRCs. The genetic differences between LS and sporadic CRCs were studied with whole exome sequencing analysis.Results:The incidence of dMMR in Chinese patients with CRCs was 13.8%. Consistency analysis between MMR immunohistochemistry (IHC) and MSI testing showed the kappa value was 0.758. With next-generation sequencing (NGS), germline variants were detected in 154 CRCs. Finally, 88 patients with CRC were identified as having LS by Sanger sequencing. Among them, we discovered 21 previously unreported pathogenic germline variants of MMR genes. Chinese patients with LS, compared with sporadic CRCs, tended to be early-onset, right-sided, early-stage and mucinous. Overall, the performance of MMR IHC and MSI testing for LS pre-screening was comparable: the area under the ROC curve for dMMR, MSI-H, and MSI-H/L was 0.725, 0.750, and 0.745, respectively. dMMR_MSI-H LS and sporadic CRCs showed substantial differences in somatic genetic characteristics, including different variant frequencies of APC, CREBBP, and KRAS, as well as different enriched pathways of VEGF, Notch, TGFβR, mTOR, ErbB, and Rac protein signal transduction.Conclusions:MMR IHC and MSI testing were effective methods for LS pre-screening. The revealed clinical and somatic genetic characteristics in LS CRCs may have the potential to improve the performance of LS pre-screening in combination with dMMR/MSI.

A pancancer analysis of KRAS alterations in Chinese population.

e15127 Background: Kirsten rat sarcoma viral oncogene homologue (KRAS) is the most frequently mutated oncogene in human cancers. Sotorasib (AMG 510) has shown promising anticancer activity in patients with heavily pre-treated KRAS p.G12C mutant solid tumors. Here, we provide an overview of genomic diversity of KRAS alterations in a large cohort of Chinese patients. Methods: Molecular profiles of 16,654 tumor specimens were obtained using gene-panel target-capture next-generation sequencing, and classified based on the presence and subtypes of KRAS mutation. Tumor mutation burdens (TMB) were calculated using an Acornmed panel with 808 cancer-related genes. Results: In total,15.04% (2505/16654) of pan-cancer patients harbored RAS mutations, and 13.58% (2262/16654) patients carried KRAS mutations in the current study. Five main subtypes of KRAS mutation were detected including G12D (642, 28.38%), G12V (392, 17.33%), G12C (354, 15.65%), G13 (220, 9.73%), G12A (101, 4.47%). In our cohort, the highest KRAS G12C mutation frequency tumor type was lung cancer (12.33%) followed by colorectal cancer (1.99%), which is comparable with the previously published data. Among all patients with KRAS G12C mutation, 77.40% (274/354) of the patients were male and 22.60% (80/354) were female. Tumor mutation burdens (TMB) were calculated for 151 samples of all the 352 KRAS G12C mutation samples. The median TMB was 10.15 mut/Mb with 50.99%≥10 mut/Mb and 14.57%≥20 mut/Mb. However, according to the results of CodeBreaK 100 exploratory analysis at the 2021 ASCO annual meeting, among all patients with KRAS G12C mutation, 17.86% of the patients had ≥ 10 mut /Mb, which was defined as TMB-high. Therefore, it can be found that the TMB of domestic and foreign patients is different. Conclusions: Genomic alterations in KRAS are widespread among Chinese pan-cancer patients. Results of CodeBreaK 100 exploratory analysis presented at the 2021 ASCO Annual Meeting showed no significant difference (40% vs 42%) in objective response rates between TMB high (≥ 10 mut/Mb) and TMB low (&lt; 10 mut/Mb). Based on our data, the threshold of TMB high in the Chinese population should be higher. The molecular marker exploration of AMG 510 efficacy in the Chinese population needs to be further carried out and confirmed.

Bone impairment in a large cohort of Chinese patients with tumor-induced osteomalacia assessed by HR-pQCT and TBS

Bone impairment in a large cohort of Chinese patients with tumor-induced osteomalacia assessed by HR-pQCT and TBS