Background: Increased nuchal translucency (NT) is an important biomarker associated with increased risk of fetal structural anomalies. It is known to be contributed by a wide range of genetic etiologies from single-nucleotide variants to those affecting millions of base pairs. Currently, prenatal diagnosis is routinely performed by karyotyping and chromosomal microarray analysis (CMA); however, both of them have limited resolution. The diversity of the genetic etiologies warrants an integrated assay such as genome sequencing (GS) for comprehensive detection of genomic variants. Herein, we aim to evaluate the feasibility of applying GS in prenatal diagnosis for the fetuses with increased NT. Methods: We retrospectively applied GS (> 30-fold) for fetuses with increased NT (≥3.5 mm) who underwent routine prenatal diagnosis. Detection of single-nucleotide variants, copy number variants, and structural rearrangements was performed simultaneously, and the results were integrated for interpretation in accordance with the guidelines of the American College of Medical Genetics and Genomics. Pathogenic or likely pathogenic (P/LP) variants were selected for validation and parental confirmation, when available. Results: Overall, 50 fetuses were enrolled, including 34 cases with isolated increased NT and 16 cases with other fetal structural malformations. Routine CMA and karyotyping reported eight P/LP CNVs, yielding a diagnostic rate of 16.0% (8/50). In comparison, GS provided a twofold increase in diagnostic yield (32.0%, 16/50), including one mosaic turner syndrome, eight cases with microdeletions/microduplications, and seven cases with P/LP point mutations. Moreover, GS identified two cryptic insertions and two inversions. Follow-up study further demonstrated the potential pathogenicity of an apparently balanced insertion that disrupted an OMIM autosomal dominant disease-causing gene at the insertion site. Conclusions: Our study demonstrates that applying GS in fetuses with increased NT can comprehensively detect and delineate the various genomic variants that are causative to the diseases. Importantly, prenatal diagnosis by GS doubled the diagnostic yield compared with routine protocols. Given a comparable turnaround time and less DNA required, our study provides strong evidence to facilitate GS in prenatal diagnosis, particularly in fetuses with increased NT.
Introduction: China continues to rank among one of the countries with the highest number of tuberculosis (TB) cases globally. Migrants are a particularly at-risk subgroup for TB and pose a challenge for case management in contemporary China. The early diagnosis and treatment of patients with TB are pivotal for effective TB control. This study investigates the delay in the TB diagnosis of migrants as compared with residents, to provide an evidence base for improved case detection and the better management of migrant patients with TB.Materials and Methods: The data was collected from the Tuberculosis Information Management System (TBIMS) (2015–2019) in an eastern county of China. The total diagnostic delay, consisting of patient delay and health system delay, is defined as the interval between the onset of TB symptoms and the confirmation of TB diagnosis in the designated TB hospital. The comparison of the delay in the TB diagnosis between migrants and residents was conducted using a Mann-Whitney U-test and chi-square test. The difference in the delay curves between these two groups was examined using a log-rank test.Results: Of 2,487 patients with TB, 539 (22%) were migrants. The migrants tended to be younger, presented with less severe conditions, received an initial diagnosis at prefectural and above-level hospitals. Compared with the local patients with TB, the migrant patients with TB had a longer median total diagnostic delay (30 vs. 9, P = 0.000) and a higher proportion of patients with this delay >28 days (52 vs. 13%, P = 0.000). Similarly, the migrant patients with TB also had a longer median patient delay (13 vs. 9, P = 0.000) and a higher proportion of patients with this delay >14 days (47 vs. 30%, P = 0.000), longer median health system delay (9 vs. 0, P = 0.000), and a higher proportion of patients with this delay >14 days (42 vs. 0.5%, P = 0.000) than the local patients with TB. The survival curves of delay showed that the longer the time interval was, the more likely the migrant patients with TB were to be diagnosed (P < 0.05).Conclusions: Diagnosis is significantly delayed among migrant patients with TB. Our study highlights the importance of early screening and diagnosis for TB especially among migrants, to improve access and ensure better management for all patients with TB.
1 Background: 2 Increased Nuchal Translucency (NT) is an important biomarker associated with increased 3 risk of fetal structural anomalies. It is known to be contributed by a wide range of genetic 4 etiologies from single nucleotide variants to those affecting millions of base-pairs. 5 Currently, prenatal diagnosis is routinely performed by karyotyping and chromosomal 6 microarray analysis (CMA), however, both of them have limited resolution. The diversity 7 of the genetic etiologies warrants an integrated assay such as genome sequencing (GS) 8for comprehensive detection of genomic variants. Herein, we aim to evaluate the 9 feasibility of applying GS in prenatal diagnosis for the fetuses with increased NT.
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