May 2024
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3 Reads
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May 2024
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3 Reads
May 2024
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10 Reads
Journal of Translational Medicine
Background Facioscapulohumeral muscular dystrophy (FSHD) is a high-prevalence autosomal dominant neuromuscular disease characterized by significant clinical and genetic heterogeneity. Genetic diagnosis of FSHD remains a challenge because it cannot be detected by standard sequencing methods and requires a complex diagnosis workflow. Methods We developed a comprehensive genetic FSHD detection method based on Oxford Nanopore Technologies (ONT) whole-genome sequencing. Using a case–control design, we applied this procedure to 29 samples and compared the results with those from optical genome mapping (OGM), bisulfite sequencing (BSS), and whole-exome sequencing (WES). Results Using our ONT-based method, we identified 59 haplotypes (35 4qA and 24 4qB) among the 29 samples (including a mosaic sample), as well as the number of D4Z4 repeat units (RUs). The pathogenetic D4Z4 RU contraction identified by our ONT-based method showed 100% concordance with OGM results. The methylation levels of the most distal D4Z4 RU and the double homeobox 4 gene (DUX4) detected by ONT sequencing are highly consistent with the BSS results and showed excellent diagnostic efficiency. Additionally, our ONT-based method provided an independent methylation profile analysis of two permissive 4qA alleles, reflecting a more accurate scenario than traditional BSS. The ONT-based method detected 17 variations in three FSHD2-related genes from nine samples, showing 100% concordance with WES. Conclusions Our ONT-based FSHD detection method is a comprehensive method for identifying pathogenetic D4Z4 RU contractions, methylation level alterations, allele-specific methylation of two 4qA haplotypes, and variations in FSHD2-related genes, which will all greatly improve genetic testing for FSHD.
January 2024
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19 Reads
Diagnostics
Optical genome mapping (OGM) has been known as an all-in-one technology for chromosomal aberration detection. However, there are also aberrations beyond the detection range of OGM. This study aimed to report the aberrations missed by OGM and analyze the contributing factors. OGM was performed by taking both GRCh37 and GRCh38 as reference genomes. The OGM results were analyzed in blinded fashion and compared to standard assays. Quality control (QC) metrics, sample types, reference genome, effective coverage and classes and locations of aberrations were then analyzed. In total, 154 clinically reported variations from 123 samples were investigated. OGM failed to detect 10 (6.5%, 10/154) aberrations with GRCh37 assembly, including five copy number variations (CNVs), two submicroscopic balanced translocations, two pericentric inversion and one isochromosome (mosaicism). All the samples passed pre-analytical and analytical QC. With GRCh38 assembly, the false-negative rate of OGM fell to 4.5% (7/154). The breakpoints of the CNVs, balanced translocations and inversions undetected by OGM were located in segmental duplication (SD) regions or regions with no DLE-1 label. In conclusion, besides variations with centromeric breakpoints, structural variations (SVs) with breakpoints located in large repetitive sequences may also be missed by OGM. GRCh38 is recommended as the reference genome when OGM is performed. Our results highlight the necessity of fully understanding the detection range and limitation of OGM in clinical practice.
December 2023
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4 Reads
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1 Citation
Clinica Chimica Acta
December 2023
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3 Reads
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1 Citation
American Journal of Obstetrics and Gynecology
November 2023
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8 Reads
Background: Copy number variants of uncertain significance (VUS) has brought much distress for patients and great counselling challenges for clinicians. Of these, a special type of VUS (HT-VUS), harbouring one or both breakpoints within the established haploinsufficient or triplosensitive genes, were considered to be more likely to cause clinical effects compared with other types of VUS. Methods: We retrospectively evaluated the properties and clinical significance of those HT-VUS samples in clinical testing for chromosome microarray analysis (CMA). Results: A total of 7150 samples were selected for HT-VUS screening, and 75 (1.05%) subjects with 75 HT-VUS were found. The majority of these HT-VUS were heterozygous duplications and chromosome X had the most HT-VUS. The prevalence of HT-VUS was 0.90% (28/3116) for prenatal low-risk samples, 1.18% (26/2196) for prenatal high-risk samples, 1.37% (10/728) for postnatal samples and 0.99% (11/1110) for early pregnancy loss samples. However, the incidence of HT-VUS was not statistically different between different groups. Conclusions: HT-VUS (deletions or duplications) involving introns and HT-VUS (duplications) including terminal coding exons (either the first or last exons) might be clinically neutral. Our study will be helpful for both interpretation and genetic counselling in the future.
October 2023
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10 Reads
Journal of Assisted Reproduction and Genetics
Chromosomal microarray analysis (CMA) has been widely applied to explore the genetic etiology in recurrent pregnancy loss (RPL). However, the reproductive prognosis in RPL couples with different types of chromosomally abnormal miscarriage remains unclear. The main purpose of this study was to evaluate the reproductive prognosis among RPL couples after genetic testing in products of conception (POCs) by CMA. In this retrospective study, 1101 RPL couples referred for genetic testing in POCs by CMA. A total of 830 couples who met the inclusion criteria were followed up for at least 24 months after the index miscarriage. The rates of live birth and adverse pregnancy events in subsequent pregnancy and cumulative pregnancies were examined. For couples with three or more miscarriage, compared with those with chromosomally normal miscarriage, a significantly higher subsequent live birth rate was found in couples with chromosomally abnormal miscarriage (66.9% vs 71.6%, P = .040). However, differences in cumulative live birth rate among couples with chromosomally abnormal miscarriage and normal miscarriage were nonsignificant (82.7% vs 80.2%, P = .131). Women with advanced maternal age showed a significant decrease in the live birth rate (P < 0.01) and an increase in the miscarriage rate (P < 0.01) than those aged < 35 years old, regardless of whether the miscarriage was chromosomally normal or abnormal. RPL couples with chromosomally normal miscarriage showed a significant decrease in live birth rates in subsequent pregnancy and cumulative pregnancies, when they had experienced a large number of previous miscarriages; however, no significant difference was observed in those with chromosomally abnormal miscarriage. For women with three or more previous miscarriages, RPL couples with chromosomally normal miscarriage manifested a poorer reproductive prognosis than those with chromosomally abnormal miscarriage in subsequent pregnancy, while the cumulative live birth rate was similar. Advanced maternal age was a predictor of adverse pregnancy events, regardless of embryonic chromosomal results. Furthermore, among RPL women with large numbers of previous miscarriages, the supportive care and counselling regarding individual risk is necessary for those with chromosomally normal miscarriage.
July 2023
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33 Reads
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2 Citations
Background: We describe a 13-year-old girl with a 11q13.3q13.4 deletion encompassing the SHANK2 gene and a 9q21.13q21.33 duplication. She presented with pre- and postnatal growth retardation, global developmental delay, severe language delay, cardiac abnormalities, and dysmorphisms. Her maternal family members all had histories of reproductive problems. Methods: Maternal family members with histories of reproductive problems were studied using G-banded karyotyping and optical genome mapping (OGM). Long-range PCR (LR-PCR) and Sanger sequencing were used to confirm the precise break point sequences obtained by OGM. Results: G-banded karyotyping characterized the cytogenetic results as 46,XX,der(9)?del(9)(q21q22)t(9;14)(q22;q24),der(11)ins(11;?9)(q13;?q21q22),der(14)t(9;14). Using OGM, we determined that asymptomatic female family members with reproductive problems were carriers of a four-way balanced chromosome translocation. Their karyotype results were further refined as 46,XX,der(9)del(9)(q21.13q21.33)t(9;14)(q21.33;q22.31),der(11)del(11)(q13.3q13.4)ins(11;9)(q13.3;q21.33q21.13),der(14)t(9:14)ins(14;11)(q23.1;q13.4q13.3). Thus, we confirmed that the affected girl inherited the maternally derived chromosome 11. Furthermore, using LR-PCR, we showed that three disease-related genes (TMC1, NTRK2, and KIAA0586) were disrupted by the breakpoints. Conclusions: Our case highlights the importance of timely parental origin testing for patients with rare copy number variations, as well as the accurate characterization of balanced chromosomal rearrangements in families with reproductive problems. In addition, our case demonstrates that OGM is a useful clinical application for analyzing complex structural variations within the human genome.
June 2023
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70 Reads
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6 Citations
Introduction Chromosomal aberrations are the most important etiological factors for birth defects. Optical genome mapping is a novel cytogenetic tool for detecting a broad range of chromosomal aberrations in a single assay, but relevant clinical feasibility studies of optical genome mapping in prenatal diagnosis are limited. Material and methods We retrospectively performed optical genome mapping analysis of amniotic fluid samples from 34 fetuses with various clinical indications and chromosomal aberrations detected through standard‐of‐care technologies, including karyotyping, fluorescence in situ hybridization, and/or chromosomal microarray analysis. Results In total, we analyzed 46 chromosomal aberrations from 34 amniotic fluid samples, including 5 aneuploidies, 10 large copy number variations, 27 microdeletions/microduplications, 2 translocations, 1 isochromosome, and 1 region of homozygosity. Overall, 45 chromosomal aberrations could be confirmed by our customized analysis strategy. Optical genome mapping reached 97.8% concordant clinical diagnosis with standard‐of‐care methods for all chromosomal aberrations in a blinded fashion. Compared with the widely used chromosomal microarray analysis, optical genome mapping additionally determined the relative orientation and position of repetitive segments for seven cases with duplications or triplications. The additional information provided by optical genome mapping will be conducive to characterizing complex chromosomal rearrangements and allowing us to propose mechanisms to explain rearrangements and predict the genetic recurrence risk. Conclusions Our study highlights that optical genome mapping can provide comprehensive and accurate information on chromosomal aberrations in a single test, suggesting that optical genome mapping has the potential to become a promising cytogenetic tool for prenatal diagnosis.
March 2023
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23 Reads
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2 Citations
Objectives Chromosomal microarray analysis (CMA) has been widely applied to genetic diagnosis in miscarriages in clinical practice. However, the prognostic value of CMA testing of products of conception (POCs) after the first clinical miscarriage remains unknown. The aim of this study was to evaluate the reproductive outcomes after embryonic genetic testing by CMA in SM couples. Methods In this retrospective study, a total of 1142 SM couples referred for embryonic genetic testing by CMA, and 1022 couples were successfully followed up after CMA. Results Among 1130 cases without significant maternal cell contamination, pathogenic chromosomal abnormalities were detected in 680 cases (60.2%). The subsequent live birth rate did not differ significantly between couples with chromosomally abnormal and normal miscarriage (88.6% vs. 91.1%, p = .240), as well as the cumulative live birth rate (94.5% vs. 96.7%, p = .131). Couples with partial aneuploid miscarriage had a higher likelihood of spontaneous abortion both in the subsequent pregnancy (19.0% vs. 6.5%, p = .037) and cumulative pregnancies (19.0% vs. 6.8%, p = .044) when compared with couples with chromosomally normal miscarriage. Conclusions SM couples with chromosomally abnormal miscarriage manifested with a similar reproductive prognosis to couples with chromosomally normal miscarriage. Key messages CMA testing of POCs could provide an accurate genetic diagnosis for couples with SM. The live birth rate of couples with partial aneuploid miscarriage was as high as couples with chromosomally normal miscarriage, despite a higher risk of adverse pregnancy event. Among couples with the most common single aneuploid miscarriage, the cumulative live birth rates of couples with trisomy 16, sex chromosomal abnormalities and trisomy 22 were 94.1%, 95.8% and 84.0%, respectively.
... OGM is a promising technology that can identify major classes of SVs in a single assay. It has been reported that OGM not only has advantage in detecting intragenic CNVs and cryptic and/or complex chromosomal rearrangements but can also perform breakpoint analysis, which is vital for interpretation of the clinical significance of SVs [17,18]. OGM has begun to be applied in prenatal and postnatal settings due to these significant advantages. ...
December 2023
American Journal of Obstetrics and Gynecology
... OGM is a promising technology that can identify major classes of SVs in a single assay. It has been reported that OGM not only has advantage in detecting intragenic CNVs and cryptic and/or complex chromosomal rearrangements but can also perform breakpoint analysis, which is vital for interpretation of the clinical significance of SVs [17,18]. OGM has begun to be applied in prenatal and postnatal settings due to these significant advantages. ...
July 2023
... OGM is an emerging and promising cytogenomic technology that has the potential to detect major classes of SVs [3]. Combining microfluidics, automated image analysis and high-resolution microscopy, OGM allows us to detect insertions and deletions above 500 bp in length and other SVs above 30 kbp in length [4]. There are two distinct algorithms. ...
June 2023
... There is a limited number of studies that have investigated the possibilities that WGS may offer in prenatal diagnosis of congenital malformation. The overall diagnostic yield, including variants detectable with CMA, of the more comprehensive WGS studies has varied from 15% (n = 185, fetuses with structural anomalies) 16 to 20% (n = 111, fetuses with structural or growth anomalies) 17 and to 46% (n = 295; n = 281 fetuses with structural anomalies, n = 14 testing due to advanced maternal age) 18 , with higher yields obtained in a research setting. ...
March 2023
American Journal of Obstetrics and Gynecology
... In contrast to the previous study by Xia Z. et al. [20], which reported a similar reproductive prognosis for couples with various types of embryonic chromosomal results after a sporadic miscarriage, the current study focused on reproductive outcomes after recurrent miscarriages. We found that the prognosis in the subsequent pregnancy was worse for couples with chromosomally normal miscarriage than for those with chromosomally abnormal miscarriage. ...
March 2023
... Lung cancer consistently ranks as the leading cause of global cancer-related mortality (1,2), with lung squamous cell carcinoma (LUSC) exhibiting a heightened propensity for metastasis and recurrence (3)(4)(5). In recent years, molecular targeted therapy has substantially enhanced the survival rates of patients afflicted with various malignancies. ...
July 2022
Cell and Tissue Research
... By comparing patients' data, it is possible to identify specific pathways that may become therapeutic targets for personalised care. Similarly, these new sciences might predict the development of diseases since foetal age, or, in borderline cases, discriminate the outcome of these patients [60,61]. ...
June 2021
... It also remains controversial [5]. Recent publications offer useful insight into patient perception, willingness-to-pay and decision-making regarding recessive disorders [6,7]. ...
January 2021
Journal of Assisted Reproduction and Genetics
... Therefore, HLPA provides an accurate, rapid, and inexpensive method for chromosome analysis of miscarriage in clinical practice. 8,9 In the present study, HLPA was used to analyze the copy numbers in 265 spontaneous abortion tissues, in order to explore the relationship between spontaneous abortion and embryonic chromosomal abnormalities. The findings could provide important guidance for genetic counseling and improving preconception preparation for couples with spontaneous abortion. ...
January 2021
Journal of Molecular Diagnostics
... It acts synergistically to dysregulate NFATc transcription factors, which are regulators of vertebrate development [51,52]. These changes are linked to intellectual disability, speech development and autism, potentially explaining some of the phenotypical features of DS [51][52][53]. Methylation of REST binding sites during early development may contribute to a genome-wide excess of hypermethylated sites. There was upregulation of DNMT3L, which is hypothesised to lead to de novo methylation of neuroprogenitors, persisting in the fetal DS brain, while DNMT3A and DNMT3B are downregulated in DS. ...
November 2019