Thalassemia and hemoglobinopathy are two common inherited disorders, which are highly prevalent in southern China. However, there is little knowledge on the genotypes of thalassemia and hemoglobinopathy in Southeastern China. In this study, we present a large-scale genetic detection and molecular characterization of thalassemia and hemoglobinopathy in Fujian province, Southeastern China. A total of 189414 subjects screened for thalassemia were recruited, and the hemoglobin components and levels were investigated. Furthermore, suspected common thalassemia was identified, and the suspected rare forms of common thalassemias and hemoglobinopathy were detected. Among the total subjects screened, the overall prevalence of thalassemia and hemoglobinopathy was 6.8% and 0.26%, and rare α-thalassemia genotypes HKαα, – THAI /αα and −α 27.6 /αα, and novel β-thalassemia gene mutations CD90(G → T) and IVS-I-110(G > A) were identified. Additionally, Hb Q-Thailand hemoglobinopathy and five other types of hemoglobinopathies (Hb New York, Hb J-Bangkok, Hb G-Taipei, Hb G-Coushatta and Hb Maputo) were found. The results of this 10-year large-scale study demonstrate high prevalence of thalassemia with complicated gene mutations in Southeastern China, which provides valuable baseline data for genetic counseling and prenatal diagnosis. In addition to detection of common thalassemia genes, detection of rare thalassemia genotypes and hemoglobinopathies is recommended.

Embryonic miscarriage severely affects the life quality and physical and mental state of pregnant women. However, the detailed mechanism underlying embryonic miscarriage is not fully understood. This study is aimed at analyzing embryonic miscarriage. We collected samples from 25 normal pregnant women and 25 embryonic miscarriage patients of similar age to analyze microbiota isolated from the vagina. Crude examination of the vagina isolates showed that compared with the control group, 80% of the embryonic miscarriage group contained a significantly lower number of Lactobacillus, the major healthy microbe in the vagina. Furthermore, the levels of Th1 and Th2 secreted cytokine interleukin 2 (IL-2) and interleukin10 (IL-10), respectively, were examined. Results showed that the IL2 level was higher, and IL10 level was lower in the embryonic miscarriage group than in the control group, whereas the IL2/IL10 level was higher in the embryonic miscarriage group than in the control group. This finding suggested that the immune response was suppressed in the embryonic miscarriage group. To further dissect the microbiota of the vagina in the two groups, 16S rDNA sequencing was performed. Bioinformatics analysis showed that 1096 and 998 overlapped operational taxonomic units were identified from the embryonic miscarriage and control groups, respectively. At the genus level, the relative abundance of Fam_Finegoldia, Lac_Coprococcus_3, and Lac_Roseburia significantly differed in the embryonic miscarriage group. Overall, our analyses provided potential biomarkers for embryonic miscarriage and elucidated the causative relationship between microbiota and immune responses and may enable the possible diagnosis and therapeutics of early pregnancy loss.

Etiopathogenesis of fetal ventriculomegaly is poorly understood. Associations between fetal isolated ventriculomegaly and copy number variations (CNVs) have been previously described. We investigated the correlations between fetal ventriculomegaly—with or without other ultrasound anomalies—and chromosome abnormalities. 222 fetuses were divided into four groups: (I) 103 (46.4%) cases with isolated ventriculomegaly, (II) 41 (18.5%) cases accompanied by soft markers, (III) 33 (14.9%) cases complicated with central nervous system (CNS) anomalies, and (IV) 45 (20.3%) cases with accompanying anomalies. Karyotyping and single nucleotide polymorphism (SNP) array were used in parallel. Karyotype abnormalities were identified in 15/222 (6.8%) cases. Karyotype abnormalities in group I, II, III, and IV were 4/103 (3.9%), 2/41 (4.9%), 4/33 (12.1%), and 5/45 (11.1%), respectively. Concerning the SNP array analysis results, 31/222 (14.0%) were CNVs, CNVs in groups I, II, III, and IV were 11/103 (10.7%), 6/41 (14.6%), 9/33 (27.3%), and 5/45 fetuses (11.1%), respectively. Detections of clinical significant CNVs were higher in non-isolated ventriculomegaly than in isolated ventriculomegaly (16.81% vs 10.7%, P = 0.19). SNP arrays can effectively identify CNVs in fetuses with ventriculomegaly and increase the abnormal chromosomal detection rate by approximately 7.2%, especially ventriculomegaly accompanied by CNS anomalies.

BackgroundThis study aimed to evaluate the feasibility of chromosomal microarray analysis (CMA) in detecting the origin and structure of small supernumerary marker chromosomes (sSMCs) in prenatal and postnatal cases and to clarify sSMC-related genotype-phenotype correlations.ResultsThirty-three cases carrying sSMCs were identified by banding cytogenetics. Of these cases, twenty-nine were first characterized by CMA and only two by FISH. The remaining two cases were excluded for their refusal to accept further examination. The chromosomal origins of twenty-two cases were successfully identified, in which pathogenetic copy number variations (PCNVs) were found in sixteen cases, four cases showed variants of uncertain significance (VOUS), one case showed benign CNVs, and one case showed probable PCNVs. For the nine cases with negative CMA results, only one of them contained centromere heterochromatin likely due to its normal phenotype, whereas reasons for the remaining eight cases were uncertain. We also found that CMA results indicating pathogenic abnormalities further affect the rate of pregnancy termination.ConclusionsThis study showed that CMA combined with cytogenetic analysis is particularly effective in identifying sSMCs. However, in order to establish sSMC-related genotype-phenotype correlations, the inclusion of more sSMC cases will be necessary in future studies.

Noninvasive prenatal testing (NIPT) is widely used to screen for common fetal chromosomal aneuploidies. However, the ability of NIPT-Plus to detect copy number variation (CNV) is debatable. Accordingly, we assessed the efficiency of NIPT-Plus to detect clinically significant fetal CNV. We performed a prospective analysis of 31,260 singleton pregnancies, included from June 2017 to December 2020. Cell-free fetal DNA was directly sequenced using the semiconductor sequencing platform for women with high-risk CNV with clinically significant results. Fetal karyotyping and chromosomal microarray analysis (or next-generation sequencing) are recommended for invasive diagnostic procedures. Women at low risk with no other abnormal results continued their pregnancies. We analyzed the expanded NIPT results, diagnostic test results, and follow-up information to evaluate its performance in detecting fetal CNV. Of the 31,260 pregnant women who received NIPT-Plus, 31,256 cases were tested successfully, a high risk of clinically significant CNV was detected in 221 cases (0.71%); 18 women refused further diagnosis; 203 women underwent invasive prenatal diagnosis; and 78 true positive cases and 125 false positive cases, with an overall positive predictive value (PPV) of 38.42% and a false positive rate of 0.40%. For known microdeletion/microduplication syndromes (n = 27), the PPVs were 75% DiGeorge syndrome (DGS), 80% 22q11.22 microduplication, 50% Prader–Willi syndrome, and 50% cri-du-chat. For the remaining clinically significant fetal CNVs (n = 175), the combined PPVs were 46.5% (CNVs > 10 Mb) and 28.57% (CNVs ≤ 10 Mb). NIPT-Plus screening for CNV has certain clinical value. NIPT-Plus yielded relatively high PPVs for 22q11.2 microduplication syndrome and DGS, and low to moderate PPVs for other CNVs.