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* Context.--Identification of rare thalassemia variants requires a combination of multiple diagnostic technologies. Objective.--To investigate a new approach of comprehensive analysis of thalassemia alleles based on third-generation sequencing (TGS) for identification of [alpha]- and [beta]-globin gene variants. Design.--Enrolled in this study were 70 suspected carriers of rare thalassemia variants. Routine gap-polymerase chain reaction and DNA sequencing were used to detect rare thalassemia variants, and TGS technology was performed to identify [alpha]- and [beta]-globin gene variants. Results.--Twenty-three cases that carried rare variants in [alpha]- and [beta]-globin genes were identified by the routine detection methods. TGS technology yielded a 7.14% (5 of 70) increment of rare [alpha]- and [beta]-globin gene variants as compared with the routine methods. Among them, the rare deletional genotype of-THAI was the most common variant. In addition, rare variants of CD15 (G>A) (HBA2:c.46G>A), CD117/118(+TCA) (HBA1:c.354_355insTCA), and [beta]-thalassemia 3.5-kilobase gene deletion were first identified in Fujian Province, China; to the best of our knowledge, this is the second report in the Chinese population. Moreover, HBA1:c.-24C>G, IVS-II-55 (G>T) (HBA1:c.300+55G>T) and hemoglobin (Hb) Maranon (HBA2:c.94A>G) were first identified in the Chinese population. We also identified rare Hb variants of HbC, HbG-Honolulu, Hb Miyashiro, and HbG-Coushatta in this study. Conclusions.--TGS technology can effectively and accurately detect deletional and nondeletional thalassemia variants simultaneously in one experiment. Our study also demonstrated the application value of TGS-based comprehensive analysis of thalassemia alleles in the detection of rare thalassemia gene variants. doi: 10.5858/arpa.2021-0510-OA, Thalassemia is a common inherited blood disorder resulting from deficient synthesis of globin chains. (1) According to the deficiency of globin genes, thalassemia can be classified into [alpha], [beta], [delta], [...]

Background: Pathogenic copy number variants (pCNVs) are associated with fetal ultrasound anomalies, which can be efficiently identified through chromosomal microarray analysis (CMA). The primary objective of the present study was to enhance understanding of the genotype–phenotype correlation in fetuses exhibiting absent or hypoplastic nasal bones using CMA. Methods: Enrolled in the present study were 94 cases of fetuses with absent/hypoplastic nasal bone, which were divided into an isolated absent/hypoplastic nasal bone group (n = 49) and a non‐isolated group (n = 45). All pregnant women enrolled in the study underwent karyotype analysis and CMA to assess chromosomal abnormalities in the fetuses. Results: Karyotype analysis and CMA detection were successfully performed in all cases. The results of karyotype and CMA indicate the presence of 11 cases of chromosome aneuploidy, with trisomy 21 being the most prevalent among them. A small supernumerary marker chromosome (sSMC) detected by karyotype analysis was further interpreted as a pCNV by CMA. Additionally, CMA detection elicited three cases of pCNVs, despite normal findings in their karyotype analysis results. Among them, one case of Roche translocation was identified to be a UPD in chromosome 15 with a low proportion of trisomy 15. Further, a significant difference in the detection rate of pCNVs was observed between non‐isolated and isolated absent/hypoplastic nasal bone (24.44% vs. 8.16%, p <.05). Conclusion: The present study enhances the utility of CMA in diagnosing the etiology of absent or hypoplastic nasal bone in fetuses. Further, isolated cases of absent or hypoplastic nasal bone strongly suggest the presence of chromosomal abnormalities, necessitating genetic evaluation through CMA. [ABSTRACT FROM AUTHOR]

Objective. Increasingly rare thalassemia has been identified with the advanced use of long-read sequencing based on long-read technology. Here, we aim to present a novel δ/β-globin gene deletion identified by long-read sequencing technology. Methods. Enrolled in this study was a family from the Quanzhou region of Southeast China. Routine blood analysis and hemoglobin (Hb) capillary electrophoresis were used for hematological screening. Genetic testing for common α- and β-thalassemia was carried out using the reverse dot blot hybridization technique. Long-read sequencing was performed to detect rare globin gene variants. Specific gap-polymerase chain reaction (gap-PCR) and/or Sanger sequencing were further used to verify the detected variants. Results. None of the common α- and β-thalassemia mutations or deletions were observed in the family. However, decreased levels of MCV, MCH, and abnormal Hb bands were observed in the family members, who were suspected as rare thalassemia carriers. Further, long-read sequencing demonstrated a large novel 7.414 kb deletion NG_000007.3:g.63511_70924del partially cover HBB and HBD globin genes causing delta-beta fusion gene in the proband. Parental verification indicated that the deletion was inherited from the proband's father, while none of the globin gene variants were observed in the proband's mother. In addition, the novel δ/β-globin gene deletion was further verified by gap-PCR and Sanger sequencing. Conclusion. In this study, we first present a large novel δ/β-globin gene deletion in a Chinese family using long-read sequencing, which may cause δβ-thalassemia. This study further enhances that long-read sequencing would be applied as a sharp tool for detecting rare and novel globin gene variants. [ABSTRACT FROM AUTHOR]

Background: Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome is a rare X‐linked dominant, lethal male disorder caused by mutations to the NSDHL (NAD(P)H steroid dehydrogenase‐like protein) gene. It primarily exhibits strictly unilateral congenital hemidysplasia with ichthyosiform erythroderma and ipsilateral limb defects in female individuals. Methods: A Chinese couple suffering from recurrent spontaneous abortion in male fetuses was enrolled in this study. Chromosomal microarray analysis and whole‐exome sequencing were performed for genetic etiological diagnosis. Results: A 33‐year‐old pregnant woman with recurrent spontaneous abortion was experiencing her third pregnancy with a male embryo. In this pregnancy, a miscarriage occurred at a gestational age of 10+6 weeks with no copy number variants. However, a novel mutation c.790‐6C>T in the NSDHL gene was observed in the fetus through whole‐exome sequencing (WES). Parental verification indicated that the NSDHL gene variant was inherited from the mother. Additionally, the variant in the NSDHL gene was absent in her subsequent pregnancy with a female fetus. Conclusion: In this study, we detected c.790‐6C>T, a novel variant in the NSDHL gene that results in recurrent miscarriage in males. Our study may broaden the scope of research on the NSDHL gene in CHILD syndrome and strengthens the application value of WES for the genetic etiological identification of recurrent miscarriage. [ABSTRACT FROM AUTHOR]

Background: Oculofaciocardiodental (OFCD) syndrome is an X-linked dominant syndrome caused by BCOR variants , which manifests only in females and presumed leading to male lethality. Herein, we aim to present a prenatal diagnosis for OFCD syndrome associated with a novel hemizygous variant in BCOR gene. Case presentation: A 29-year-old pregnant woman from Quanzhou Fujian Province, China, with fetal ultrasound anomalies, was enrolled in this study. A normal 46, XY karyotype with no abnormalities was observed in the fetus detected on microarray. Furthermore, a whole-exome sequencing (WES) detection result demonstrated that a novel hemizygous variant of c.251dupT (p.N87Kfs*6) in the BCOR gene was identified in the fetus, which was a frameshift mutation and classified as a likely pathogenic variant, and may lead to OFCD syndrome according to the clinical feature of the fetus. In this case, male lethality had not occurred by the end of the second trimester, then termination of the pregnancy was conducted at a gestational age of 26 weeks. Sanger sequencing of parental samples revealed that the variant was maternally transmitted, which was consistent with the OFCD syndrome phenotypic features observed in her. Conclusions: In the study, we first present the affected male with a novel variant in BCOR that leads to the OFCD syndrome. Additionally, our study broadened the spectrum of BCOR results in the OFCD syndrome and provided the valuable references for prenatal genetic consultation. [ABSTRACT FROM AUTHOR]

Shen-qi-Yi-zhu decoction (SQYZD) is an empirical prescription with antigastric cancer (GC) property created by Xu Jing-fan, a National Chinese Medical Master. However, its underlying mechanisms are still unclear. Based on network pharmacology and experimental verification, this study puts forward a systematic method to clarify the anti-GC mechanism of SQYZD. The active ingredients of SQYZD and their potential targets were acquired from the TCMSP database. The target genes related to GC gathered from GeneCards, DisGeNET, OMIM, TTD, and DrugBank databases were imported to establish protein-protein interaction (PPI) networks in GeneMANIA. Cytoscape was used to establish the drug-ingredients-targets-disease network. The hub target genes collected from the SQYZD and GC were parsed via GO and KEGG analysis. Our findings from network pharmacology were successfully validated using an in vitro HGC27 cell model experiment. In a word, this study proves that the combination of network pharmacology and in vitro experiments is effective in clarifying the potential molecular mechanism of traditional Chinese medicine (TCM). [ABSTRACT FROM AUTHOR]

The identified modal parameters in Operational Modal Analysis (OMA) are always subject to statistical uncertainties from many sources and the uncertainty is also important to assess the quality of the identified results. This study proposes an uncertainty quantification method in OMA for time-varying structures based on the Functional Series Time-dependent AutoRegressive Moving Average (FS-TARMA) model. A multi-stage pseudo-linear optimization scheme is first adopted to obtain the approximate Maximum Likelihood Estimates (MLEs) of FS-TARMA model parameters and the covariance is computed as the inverse Hessian matrix of the Negative Log-Likelihood Function (NLLF) at the MLEs. Finally, the approximate closed-form covariance of modal parameters is derived by the first-order sensitivity method. The proposed method is verified by two numerical examples and an experimental beam. Furthermore, the ability of the uncertainty to extinguish the spurious modes caused by colored noise excitation and the noise modes caused by measurement noise or inappropriate model structure is also demonstrated in these examples. • The uncertainties of modal parameters for time-varying structures are quantified. • The covariance of FS-TARMA parameters is obtained from the inverse Hessian matrix. • The first-order sensitivity method obtains the covariance of modal parameters. • The uncertainty of spurious modes caused by non-white excitation is discussed. • The uncertainty of noise modes caused by measurement noise is discussed. [ABSTRACT FROM AUTHOR]

Background: α-thalassaemia is an inherited blood disorder caused by mutations in the α-globin gene cluster. Recognizing the pathogenic α-globin gene mutations associated with α-Thalassemia is of significant importance to thalassaemia's diagnosis and management. Methods: A family with α-thalassaemia from Fujian, China was recruited for this study. The phenotype was confirmed through haematological analysis. Commercially available Gap-PCR genotypic methods were employed to identify the known deletions causing α-thalassemia. MLPA analysis was used to study the novel mutations; this was then confirmed through DNA sequencing and bioinformatics analysis. Results: The proband of the family belonged to Southeast Asian type (--SEA) thalassaemia. None of the known mutations associated with α-thalassaemia were detected in this family's genetics, whereas a novel 6.9 kb deletion (16p13.3 g.29,785-36,746) covering the α2 gene on the globin gene cluster was identified with MLPA and confirmed through Sanger Sequencing. This data led us to propose a novel pathogenic deletion associated with α-thalassemia: -α6.9 /--SEA. Conclusions: A novel α-thalassaemia deletion was identified in members of a Chinese family and subsequently analyzed. This finding has helped broaden the spectrum of pathogenic mutations leading to the development of α-thalassaemia, paving the way for improved disease diagnosis and management. [ABSTRACT FROM AUTHOR]