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Introduction: Though an increase in Hb A2 is one of the most key markers of β‐thal carriers, a few independent cases are reported to show elevated Hb A2 levels caused by mutations in other genes beyond β‐globin gene. Methods: We reviewed the haematological indices of 47336 individuals to analyse the phenotype–genotype correlation and identified 1439 individuals (3.04%) positive in the elevation of Hb A2. Globin and KLF1 genes analysis was performed, and further whole‐exome sequencing was carried to dissect the genetic causes of those positive samples without β‐thalassemic or KLF1 mutations. Results: Of these 1439 individuals with elevated Hb A2, 1381 had a molecular defect in globin genes, and most were β‐thalassemic mutation; 10 had a molecular defect in KLF1 gene. Finally, among the 38 individuals without β‐thalassemic or KLF1 mutations, 7 were identified to carried a loss‐of‐function mutation in SUPT5H. Conclusion: This study has provided a mutation spectrum of SUPT5H in a cohort screening leading to the elevation of Hb A2. According to the previous observations that individuals with a combination of β‐thal mutation and a SUPT5H variant might present moderate β‐thaelassemia, these findings emphasized the importance of comprehensive molecular diagnosis to prevent birth defects of β‐thaelassemia caused by rare mutations from modifier genes. [ABSTRACT FROM AUTHOR]

Platelet acts as a crucial monitoring indicator for hypercoagulability and thrombosis and a key target for drug regulation. Genotype-phenotype association studies have confirmed that platelet traits are quantitatively regulated by multiple genes. However, there is currently a lack of genetic studies on the heterogeneity of platelet traits in β-thalassemia under hypercoagulable state. Here, we studied the phenotypic heterogeneity of platelet count (PLT) and mean platelet volume (MPV) in 1020 β-thalassemia patients. We further performed a functionally informed whole genome sequencing association analysis of common variants and rare variants (RVs) for PLT and MPV in 916 patients through integrative analysis of whole-genome sequencing data and functional annotation data. Extreme phenotypic heterogeneity of platelet traits was observed in β-thalassemia patients. Additionally, the common variant based gene-level analysis identified the novel gene of RNF144B associated with MPV. The RV analysis identified several novel associations in both coding and noncoding genome, including missense RVs of PPP2R5C associated with PLT and missense RVs of TSSK1B associated with MPV. In conclusion, we performed a comprehensive and systematic whole genome scan of platelet traits in the β-thalassemia cohort, demonstrating the specificity of genetic regulation of platelet traits in the context of β-thalassemia, providing potential targets for intervention., (© The Author(s) 2024. Published by Oxford University Press and Science Press on behalf of the Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China.)

Introduction: Though an increase in Hb A 2 is one of the most key markers of β-thal carriers, a few independent cases are reported to show elevated Hb A 2 levels caused by mutations in other genes beyond β-globin gene., Methods: We reviewed the haematological indices of 47336 individuals to analyse the phenotype-genotype correlation and identified 1439 individuals (3.04%) positive in the elevation of Hb A 2 . Globin and KLF1 genes analysis was performed, and further whole-exome sequencing was carried to dissect the genetic causes of those positive samples without β-thalassemic or KLF1 mutations., Results: Of these 1439 individuals with elevated Hb A 2 , 1381 had a molecular defect in globin genes, and most were β-thalassemic mutation; 10 had a molecular defect in KLF1 gene. Finally, among the 38 individuals without β-thalassemic or KLF1 mutations, 7 were identified to carried a loss-of-function mutation in SUPT5H., Conclusion: This study has provided a mutation spectrum of SUPT5H in a cohort screening leading to the elevation of Hb A 2 . According to the previous observations that individuals with a combination of β-thal mutation and a SUPT5H variant might present moderate β-thaelassemia, these findings emphasized the importance of comprehensive molecular diagnosis to prevent birth defects of β-thaelassemia caused by rare mutations from modifier genes., (© 2022 John Wiley & Sons Ltd.)

Hemoglobinopathies are among the most common autosomal-recessive disorders worldwide. A comprehensive next-generation sequencing (NGS) test would greatly facilitate screening and diagnosis of these disorders. An NGS panel targeting the coding regions of hemoglobin genes and four modifier genes was designed. We validated the assay by using 2522 subjects affected with hemoglobinopathies and applied it to carrier testing in a cohort of 10,111 couples who were also screened through traditional methods. In the clinical genotyping analysis of 1182 β-thalassemia subjects, we identified a group of additional variants that can be used for accurate diagnosis. In the molecular screening analysis of the 10,111 couples, we detected 4180 individuals in total who carried 4840 mutant alleles, and identified 186 couples at risk of having affected offspring. 12.1% of the pathogenic or likely pathogenic variants identified by our NGS assay, which were undetectable by traditional methods. Compared with the traditional methods, our assay identified an additional at-risk 35 couples. We describe a comprehensive NGS-based test that offers advantages over the traditional screening/molecular testing methods. To our knowledge, this is among the first large-scale population study to systematically evaluate the application of an NGS technique in carrier screening and molecular diagnosis of hemoglobinopathies., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Dentin dysplasia I (DDI) is a genetically heterogeneous autosomal-dominant disorder characterised by rootless teeth with abnormal pulpal morphology, the aetiology of which presents as genetically heterogeneous., Methods and Results: Using a cohort of a large Chinese family with 10 patients with DDI, we mapped to a 9.63 Mb candidate region for DDI on chromosome 18q21.2-q21.33. We then identified a mutation IVS7+46C>G which resulted in a novel donor splice site in intron 7 of the VPS4B gene with co-segregation of all 10 affected individuals in this family. The aberrant transcripts encompassing a new insert of 45 bp in size were detected in gingival cells from affected individuals. Protein structure prediction showed that a 15-amino acid insertion altered the ATP-binding cassette of VPS4B. The mutation resulted in significantly reduced expression of mRNA and protein and altered subcellular localisation of VPS4B, indicating a loss of function of VPS4B. Using human gingival fibroblasts, the VPS4B gene was found to act as an upstream transducer linked to Wnt/β-catenin signalling and regulating odontogenesis. Furthermore, knockdown of vps4b in zebrafish recapitulated the reduction of tooth size and absence of teeth similar to the tooth phenotype exhibited in DDI index cases, and the zebrafish mutant phenotype could be partially rescued by wild-type human VPS4B mRNA. We also observed that vps4b depletion in the zebrafish negatively regulates the expression of some major genes involved in odontogenesis., Conclusions: This study identifies VPS4B as a disease-causing gene for DDI, which is one of the important contributors to tooth formation, through the Wnt/β-catenin signalling pathway., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: Probe into the causes of postoperative delayed hemorrhage of low temperature plasma tonsillectomy in children., Method: The methods of retrospective analysis the difference of postoperative bleeding time and bleeding rate between tonsillectomy by the low temperature plasma and the traditional cold surgical devices in 2-14 years old children. Plasma group contained the tonsillectomy by low temperature plasma between the March in 2012 to the August in 2013. Traditional group contained the tonsillectomy by traditional cold surgical devices between the March in 2005 to the August in 2006., Result: In the 1,000 cases of plasma group, 19 cases occurred postoperative hemorrhage, the hemorrhage rate was 1. 9%. Four cases occurred postoperative primary hemorrhage in 8 hours after operation, the postoperative primary hemorrhage rate was 0. 4%. Fifteen cases occurred postoperative delayed hemorrhage, the delayed hemorrhage rate was 1. 50%, the bleeding time was 2-13 days after operation, the average number was 7. 5 days. Nine cases had wound infection and 6 cases had eaten some food improperly in these 15 cases. And in these eaten improperly cases, 4 children had eaten fruit and hard food, 2 children had eaten a little food who lost their weight. In 860 cases of the traditional group, 29 cases occurred postoperative hemorrhage, the hemorrhage rate was 3. 37%. 26 cases occurred postoperative primary hemorrhage in 8 hours after operation, the postoperative primary hemorrhage rate was 3. 02%. Three cases occurred postoperative delayed hemorrhage, the delayed hemorrhage rate was 0. 35%, the bleeding time was 2-6 days, the average number was 4 days., Conclusion: It is preferable for chileren to having low temperature plasma tonsillectomy. The causes of postoperative delayed hemorrhage of low temperature plasma tonsillectomy in children are probably related to the postoperative infection, the differences of operation skills, the method of stop bleeding, eating the wrong foods, irritating cough, improper nursing and so on.