Prenatal diagnosis and genetic analysis of small supernumerary marker chromosomes in the eastern chinese han population: A retrospective study of 36 cases.

BACKGROUND: Small supernumerary marker chromosomes (sSMCs) are additional chromosomes with unclear structures and origins, and their correlations with clinical fetal phenotypes remain incompletely understood, which reduces the accuracy of genetic counseling. METHODS: We conducted a retrospective analysis of a cohort of 36 cases of sSMCs diagnosed in our center. We performed G-banding and chromosomal microarray analysis (CMA). The resulting karyotypes were compared with case reports in the literature and various databases including OMIM, DECIPHER, ClinVar, ClinGen, ISCA, DGV, and PubMed. RESULTS: Karyotype analysis data revealed that 19 out of 36 fetuses were mosaic. Copy number variants (CNVs) analysis results showed that 27 out of 36 fetuses harbored pathogenic/likely pathogenic variants. Among these 27 cases, 11 fetuses carried sex chromosome-related CNVs, including 4 female cases exhibiting Turner syndrome phenotypes and 7 cases showing Y chromosome deletions. In the remaining 16 fetuses with autosomal CNVs, 9 fetuses carried variants associated with Cat eye syndrome, Emanuel syndrome, Tetrasomy 18p, and 15q11-q13 duplication syndrome. Among these, 22 fetuses were terminated, and the remaining 5 fetuses were delivered and developed normally. Additionally, we identified a few variants with unclear pathogenicity. CONCLUSION: Cytogenetic analysis is essential for identifying the pathogenicity of sSMCs and increasing the accuracy of genetic counseling.

Regulation of N6-methyladenosine modification in erythropoiesis and thalassemia.

In eukaryotic RNA, N6-methyladenosine (m6A) is a prevalent form of methylation modification. The m6A modification process is reversible and dynamic, written by m6A methyltransferase complex, erased by m6A demethylase, and recognized by m6A binding proteins. Through mediating RNA stability, decay, alternative splicing, and translation processes, m6A modification regulates gene expression at the post-transcriptional level. Erythropoiesis is the process of hematopoietic stem cells undergoing proliferation, a series of differentiation and maturation to form red blood cells (RBCs). Thalassemia is a common monogenic disease characterized by excessive production of ineffective RBCs in the peripheral circulation, resulting in hemolytic anemia. Increasing evidence suggests that m6A modification plays a crucial role in erythropoiesis. In this review, we comprehensively summarize the function of m6A modification in erythropoiesis and further generalize the mechanism of m6A modification regulating ineffective erythropoiesis and fetal hemoglobin expression. The purpose is to improve the understanding of the pathogenesis of erythroid dysplasia and offer new perspectives for the diagnosis and treatment of thalassemia.

Peripheral blood circular RNA circ-0008102 may serve as a novel clinical biomarker in beta-thalassemia patients.

Circular RNA circ-0008102 has previously been found dysregulated in ß-thalassemia (ß-thal) in circRNAs microarray (GSE196682 and GSE241141). Our study is aimed at identifying whether circ-0008102 could be a novel biomarker in ß-thal. The peripheral blood of pediatric ß-thal patients with (n = 39) or without (n = 20) blood transfusion and healthy controls (n = 30) was selected. qRT-PCR, ROC curve analysis, Spearman correlation analysis, and FISH were used to analyze clinical value of circ-0008102. qRT-PCR confirmed that circ-0008102 expression in pediatric ß-thal patients without blood transfusion was significantly higher. ROC curves analysis showed that the AUC of circ-0008102 for differentiating patients without blood transfusion from patients with blood transfusion and healthy controls with an AUC of 0.733 and 0.711. Furthermore, circ-0008102 expression was positively correlated with the levels of RBC, HbF, ß-globin, and γ-globin mRNA, but was negatively corrected with the levels of HbA and Cr. circ-0008102 was mainly located in the cytoplasm. circ-0008102 could induce the activation of γ-globin and negatively regulate the expression of the five highest-ranking candidate miRNAs (miR-372-3p, miR-329-5p, miR-198, miR-152-5p, and miR-627-3p) in K562 cells. CONCLUSION: We demonstrate that peripheral blood upregulated circ-0008102 may serve as a novel clinical biomarker for pediatric ß-thal without blood transfusion. WHAT IS KNOWN: • CircRNAs are known to be involved in various human diseases, and several circRNAs are regarded as a class of promising blood-based biomarkers for detection of ß-thal. • CircRNAs exert biological functions by epigenetic modification and gene expression regulation, and dysregulated circRNAs in ß-thal might be involved in the induction of HbF in ß-thal. WHAT IS NEW: • Peripheral blood circ-0008102 maybe serve as a novel clinical biomarker for detection of pediatric ß-thal without blood transfusion. • Circ-0008102 participates in the pathogenesis of ß-thal through regulating γ-globin expression, and negatively regulates the expression of miR-372-3p, miR-329-5p, miR-198, miR-152-5p and miR-627-3p.

Intrauterine ultrasound phenotyping, molecular characteristics, and postnatal follow-up of fetuses with the 15q11.2 BP1-BP2 microdeletion syndrome: a single-center, retrospective clinical study.

OBJECTIVES: The 15q11.2 BP1-BP2 microdeletion is associated with neurodevelopmental diseases. However, most studies on this microdeletion have focused on adults and children. Thus, in this study, we summarized the molecular characteristics of fetuses with the 15q11.2 BP1-BP2 microdeletion and their postnatal follow-up to guide prenatal diagnosis. METHODS: Ten thousand fetuses were retrospectively subjected to karyotype analysis and chromosome microarray analysis. RESULTS: Chromosome microarray analysis revealed that 37 (0.4%) of the 10,000 fetuses had 15q11.2 BP1-BP2 microdeletions. The fragment size of the 15q11.2 BP1-BP2 region was approximately 312-855 kb and encompassed TUBGCP5, CYFIP1, NIPA2, and NIPA1 genes. Twenty-five of the 37 fetuses with this microdeletion showed phenotypic abnormalities. The most common ultrasonic structural abnormality was congenital heart disease, followed by renal dysplasia and Dandy-Walker malformation. The 15q11.2 BP1-BP2 microdeletion was inherited from the father and mother in 6 and 10 cases, respectively, and de novo inherited in 4 cases. In the postnatal follow-up, 16.1% of the children had postnatal abnormalities. CONCLUSION: Fetuses with the 15q11.2 BP1-BP2 microdeletion showed high proportions of phenotypic abnormalities, but the specificity of penetrance was low. Thus, fetuses with this syndrome are potentially at a higher risk of postnatal growth/behavioral problems and require continuous monitoring of growth and development.

Transforming growth factor-induced gene TGFBI is correlated with the prognosis and immune infiltrations of breast cancer.

BACKGROUND: Transforming growth factor ß (TGFß) is a critical regulator of lung metastasis of breast cancer and is correlated with the prognosis of breast cancer. However, not all TGFß stimulated genes were functional and prognostic in breast cancer lung metastatic progress. In this study, we tried to determine the prognosis of TGFß stimulated genes in breast cancer. METHODS: TGFß stimulated genes in MDA-MB-231 cells and lung metastasis-associated genes in LM2-4175 cells were identified through gene expression microarray. The prognosis of the induced gene (TGFBI) in breast cancer was determined through bioinformatics analysis and validated using tissue microarray. The immune infiltrations of breast cancer were determined through "ESTIMATE" and "TIMER". RESULTS: TGFBI was up-regulated by TGFß treatment and over-expressed in LM2-4175 cells. Through bioinformatics analysis, we found that higher expression of TGFBI was associated with shorted lung metastasis-free survival, relapse-free survival, disease-free survival, and overall survival of breast cancer. Moreover, the prognosis of TGFBI was validated in 139 Chinese breast cancer patients. Chinese breast cancer patients with higher TGFBI expression had lower overall survival. Correspondingly, breast cancer patients with higher TGFBI methylation had higher overall survival. TGFBI was correlated with the score of the TGFß signaling pathway and multiple immune-related signaling pathways in breast cancer. The stromal score, immune score, and the infiltrations of immune cells were also correlated with TGFBI expression in breast cancer. CONCLUSIONS: TGFß-induced gene TGFBI was correlated with the prognosis and immune infiltrations of breast cancer.

Genetic analysis, ultrasound phenotype, and pregnancy outcomes of fetuses with Xp22.33 or Yp11.32 microdeletions.

OBJECTIVES: The phenotypes of Xp22.33 or Yp11.32 microdeletions comprising the short-stature homeobox (SHOX) gene have been extensively described in adults and children. Herein, the prenatal ultrasound phenotype and pregnancy outcomes of fetuses with Xp22.33/Yp11.32 microdeletions were analyzed to improve our understanding, diagnosis, and monitoring of this genetic condition in the fetal stage. METHODS: A total of 9,100 pregnant women referred to tertiary units for prenatal diagnosis were evaluated by chromosomal microarray analysis(CMA). RESULTS: Seven (0.08 %) fetuses had Xp22.33/Yp11.32 microdeletions, ranging from 243 kb to 1.1 Mb, that comprised SHOX. The ultrasonic phenotypes differed among these fetuses, with three fetuses presenting abnormal bone development, one had labial-palatal deformity and strawberry head, two had an abnormal ultrasonic soft marker, and one had no abnormalities. After genetic counseling, only one couple underwent pedigree assessment, which confirmed the paternal origin of the microdeletion. This infant presented delayed speech development, whereas other three infants showed a typical postnatal development. In three cases, the parents chose to terminate the pregnancy. CONCLUSIONS: The ultrasonic phenotype of fetuses with Xp22.33/Yp11.32 microdeletions resulting in SHOX heterozygosity loss is variable. Prenatal CMA can quickly and effectively diagnose Xp22.33/Yp11.32 microdeletions and SHOX loss, which may help prenatal counseling.

First Report of Filipino ß0-Thalassemia/ß-Thalassemia in a Chinese Family.

A pregnant woman living in Fujian Province, southeastern China, presented due to a risk of having a baby with ß-thalassemia major, during her second pregnancy, since she and her husband were suspected as ß-thalassemia carriers and their affected daughter was a transfusion-dependent patient. Using the common α-thalassemia and ß-thalassemia genotypes test, the pregnant woman was diagnosed as a ß-thalassemia carrier with ßIVS-2 - 654 (C→T)/ßN genotype and her daughter had a homozygosity for IVS - 2 - 654 (C→T) mutation, however, no abnormalities were detected in her husband. SMRT identified a Filipino ß0-deletion in her husband, and MLPA also revealed an unknown deletion in the HBB gene. Electrophoresis showed approximately 350 bp of the PCR product, and the ß-Filipino genotype presented novel fracture fragments ranging from 5,112,884 to 5,231,358 bp, and lacked a 118,475 bp fragment relative to the wild-type sequence. The daughter was therefore diagnosed with the ßIVS-2 - 654 (C→T)/ßFilipino genotype. Prenatal diagnosis with umbilical cord blood at 27th week of gestation showed heteroztgosity for IVS - 2 - 654 (C→T) mutation in the fetus and continued pregnancy was recommended. In conclusion, we identified the Filipino ß0-deletion in a Chinese family, from Fujian area, for the first time, during prenatal screening.

[Advance of research on the role of BCL11A in the occurrence and treatment of ß-Thalassemia].

ß-Thalassemia is a single-gene disease caused by mutations in ß-globin and has a distinct geographical characteristics. Current treatment for patients with moderate to severe thalassemia has mainly relied on long-term blood transfusion and/or hematopoietic stem cell transplantation. B cell lymphoma/leukemia 11A (BCL11A) as a transcriptional repressor plays a vital role in monitoring γ/ß hemoglobin switching, maintaining the normal function of hematopoietic stem cells, and regulating erythrocyte differentiation and lymphocyte development. With the rapid progress in gene editing technology, the BCL11A as a therapeutic target for ß-thalassemia has shown promising results. This article has systematically summarized the regulatory mechanism and therapeutic potential of the BCL11A, with an aim to provide new ideas for the treatment of ß-thalassemia.

Pathogenic copy number variations are associated with foetal short femur length in a tertiary referral centre study.

Shortened foetal femur length (FL) is a common abnormal phenotype that often causes anxiety in pregnant women, and standard clinical treatments remain unavailable. We investigated the clinical characteristics, genetic aetiology and obstetric pregnancy outcomes of foetuses with short FL and provided a reference for perinatal management of such cases. Chromosomal microarray analysis was used to analyse the copy number variations (CNV) in short FL foetuses. Of the 218 foetuses with short FL, 33 foetuses exhibited abnormal CNVs, including 19 with pathogenic CNVs and 14 with variations of uncertain clinical significance. Of the 19 foetuses with pathogenic CNVs, four had aneuploidy, 14 had deletions/duplications, and one had pathogenic uniparental diploidy. The 7q11.23 microdeletion was detected in three foetuses. The severity of short FL was not associated with the rate of pathogenic CNVs. The duration of short FL for the intrauterine ultrasound phenotype in foetuses carrying a pathogenic CNV was independent of the gestational age. Further, maternal age was not associated with the incidence of foetal pathogenic CNVs. Adverse pregnancy outcomes occurred in 77 cases, including termination of pregnancy in 63 cases, postnatal dwarfed foetuses with intellectual disability in 11 cases, and three deaths within 3 months of birth. Pathogenic CNVs closely related to foetal short FL were identified, among which the 7q11.23 microdeletion was highly associated with short FL development. This study provides a reference for the perinatal management of foetuses with short FL.

A novel PLS1 c.981+1G>A variant causes autosomal-dominant hereditary hearing loss in a family.

The fimbrin protein family contains a variety of proteins, among which Plastin1 (PLS1) is an important member. According to recent studies, variations in the coding region of the PLS1 gene are associated with the development of deafness. However, the molecular mechanism of deafness caused by PLS1 gene variants remains unknown. Whole-exome sequencing was performed on hearing-impaired family members and hearing family members to identify pathogenic variants, followed by Sanger sequencing. A minigene assay was conducted to investigate the effect of the variant on PLS1 mRNA splicing. The pathogenicity of the variant was further investigated in zebrafish. RNA-sequencing (RNA-seq) was performed to analyze the dysregulation of downstream signaling pathways caused by knockdown of PLS1 expression. We identified a novel variant, PLS1 c.981+1G>A, in a large Chinese family with hearing loss and showed that the variant is responsible for the occurrence of hearing loss by inducing exon 8 skipping. The variant caused abnormal inner ear phenotypes, characterized by decreases in the mean otolith distance, anterior otolith diameter, posterior otolith diameter, cochlear diameter, and swimming speed and distance in zebrafish. Furthermore, silencing PLS1 expression significantly upregulated the expression of genes in the PI3K-Akt signaling pathway, including Col6a3, Spp1, Itgb3 and hepatocyte growth factor (Hgf). PLS1 c.981+1G>A is a novel pathogenic variant causing hearing loss by inducing exon 8 skipping. Upregulation of the expression of genes in the PI3K-Akt signaling pathway plays an important role in the pathogenesis caused by variants in the PLS1 gene.

Activating transcription factor 4 in erythroid development and [Formula: see text]-thalassemia: a powerful regulator with therapeutic potential.

Activating transcription factor 4 (ATF4) is a fundamental basic region/leucine zipper transcription factor, responds to various stress signals, and plays crucial roles in normal metabolic and stress response processes. Although its functions in human health and disease are not completely understood, compelling evidence underscores ATF4 is indispensable for multiple stages and lineages of erythroid development, including the regulation of fetal liver hematopoietic stem cells, induction of terminal erythroid differentiation, and maintenance of erythroid homeostasis. [Formula: see text]-Thalassemia is a blood disorder arising from mutations in the [Formula: see text]-globin gene. Reactivating the expression of the [Formula: see text]-globin gene in adult patients has emerged as a promising therapeutic strategy for ameliorating clinical symptoms associated with [Formula: see text]-thalassemia. Recent research has suggested that ATF4 contributes to decreased fetal hemoglobin (HbF) level through its binding to potent negative regulators of HbF, such as BCL11A and MYB. Notably, evidence also suggests a contrasting outcome where increased ATF4 protein levels are associated with enhanced HbF at the transcriptional level. Consequently, the identification of mechanisms that modulate ATF4-mediated [Formula: see text]-globin transcription and its effects on erythroid development may unveil novel targets for [Formula: see text]-thalassemia treatment.

Analysis of retest reliability for pregnant women undergoing cfDNA testing with a no-call result.

BACKGROUND: Determining the reasons for unreportable or no-call cell-free DNA (cfDNA) test results has been an ongoing issue, and a consensus on subsequent management is still lacking. This study aimed to explore potential factors related to no-call cfDNA test results and to discuss whether retest results are reliable. METHODS AND RESULTS: This was a retrospective study of women with singleton pregnancies undergoing cfDNA testing in 2021. Of the 9871 pregnant patients undergoing cfDNA testing, 111 had a no-call result, and their results were compared to those of 170 control patients. The no-call rate was 1.12% (111/9871), and the primary cause for no-call results was data fluctuation (88.29%, 98/111). Medical conditions were significantly more frequent in the no-call group than in the reportable results group (P < 0.001). After retesting, 107 (107/111, 96.40%) patients had a result, and the false-positive rate (FPR) of retesting was 10.09% (10.09%, 11/109). In addition, placental lesions were more frequent in the no-call group than in the reportable results group (P = 0.037), and 4 patients, all in the no-call group, experienced pregnancy loss. CONCLUSIONS: Pregnant women with medical conditions are more likely to have a no-call result. A retest is suggested for patients with a no-call result, but retests have a high FPR. In addition, pregnant women with a no-call result are at increased risk of adverse pregnancy outcomes. In conclusion, more attention should be given to pregnant women for whom a no-call cfDNA result is obtained.

Fetal genetic findings by chromosomal microarray analysis and karyotyping for fetal growth restriction without structural malformations at a territory referral center: 10-year experience.

BACKGROUND: Prenatal invasive genetic testing is commonly recommended to pregnancies of early-onset FGR or FGR combined with a structural defect. Our study aimed to explore the genetic findings for FGR without structural malformations according to cytogenetic karyotyping and single nucleotide polymorphism array (SNP array) technology over a 10-year period. METHODS: A total of 488 pregnancies diagnosed with FGR without structural malformation were retrospectively reviewed. Cytogenetic karyotyping was performed on all the subjects, and SNP array was available from 272 of them. Based on the gestational age at onset, the cohort was classified into four groups: ≤ 24, 25-28, 29-32, and > 32 weeks of gestation. According to the ultrasound findings, they were grouped into isolated FGR, FGR with soft markers, and FGR with non-structural anomalies. In pregnancies of young maternal age, based on the results of maternal serum screening (MSS), they were categorized into high-risk and low-risk MSS groups. RESULTS: Nineteen (3.9%) cases of chromosomal abnormalities were detected by cytogenetic karyotyping, including 11 cases of numerical abnormalities, 5 cases of structural abnormalities, and 3 cases of mosaicism. Trisomy 21 was the most frequent abnormality. Abnormal karyotypes were more frequently observed in cases diagnosed at ≤ 24 weeks (7.2%) than those in any other group. Among pregnancies with normal karyotype, an incremental yield of 4.2% were revealed by SNP array technology regarding clinically relevant aberrations. The additional detection rates by SNP array in cases diagnosed at ≤ 24 weeks (6.5%), cases with soft markers (9.5%), and cases with high-risk MSS (12.0%) were higher than those in other groups within each classification. All the cases with abnormal karyotypes and 7 out of 11 pregnancies with clinically relevant anomalies revealed by SNP array alone resulted in pregnancy terminations. CONCLUSION: Chromosome abnormality is an important etiology for FGR with no associated structural malformations, and plays a crucial role in pregnancies decision-making. SNP array improves the detection of genetic anomalies especially in FGR diagnosed at ≤ 24 weeks, FGR combined with soft makers, and FGR combined with high-risk MSS.

Prenatal diagnosis of non-mosaic sex chromosome abnormalities: a 10-year experience from a tertiary referral center.

OBJECTIVES: The aim of this study was to explore the frequency and profile of non-mosaic sex chromosome abnormalities detected in prenatal diagnosis over the past 10 years. METHODS: We retrospectively reviewed pregnancies diagnosed with non-mosaic sex chromosome abnormalities between January 2012 and December 2021, using karyotyping and/or single nucleotide polymorphism (SNP) array. Maternal age, indications for testing, and outcomes were recorded. RESULTS: Traditional karyotyping identified 269 (0.90 %) cases of non-mosaic sex chromosome abnormalities among 29,832 fetuses, including 249 cases of numerical abnormalities, 15 unbalanced structural abnormalities, and 5 balanced structural abnormalities. The overall detection rate of common sex chromosome aneuploidies (SCAs) was 0.81 %, with 47,XXY, 47,XXX, 47,XYY, and 45,X accounting for 0.32 , 0.19, 0.17, and 0.13 % respectively. All showed a fluctuating upward trend over the study period, except for 45,X. During the first five years (2012-2016), the major indication for testing was advanced maternal age (AMA), followed by abnormal ultrasound, abnormal noninvasive prenatal testing (NIPT), and abnormal maternal serum screening (MSS). In the second five years (2017-2021), the most frequent indication was abnormal NIPT, followed by AMA, abnormal ultrasound, and abnormal MSS. Among the 7,780 cases that underwent SNP array in parallel, an additional 29 clinically significant aberrations were detected. The most frequent aberration was a microdeletion in the Xp22.31 region, which was associated with X-linked ichthyosis. CONCLUSIONS: Fetal sex chromosome abnormalities are important findings in prenatal diagnosis. The application of NIPT and SNP array technology has greatly improved the detection of SCAs and submicroscopic aberrations associated with sex chromosomes.

Fetal mosaicism, should conventional karyotype always be performed?

BACKGROUND AND PURPOSE: The application of classical cytogenetic and DNA-based molecular techniques to detect cell lineages of mosaicism derived from cultured or noncultured fetal cells may result in discordant results. This retrospective study aimed to assess the inconsistent diagnostic outcomes, technical availability, and limitations of chromosomal microarray analysis (CMA) and karyotyping for mosaicism. METHODOLOGY: A total of 75 fetuses diagnosed with mosaicism by karyotype analysis or CMA were selected, and the results from both the methods were compared and further analyzed. RESULTS: A total of 42 (56%, 42/75) CMA results were consistent with karyotypes, consisting of 22 cases of mosaic sex chromosomal abnormalities, 8 routine autosomal aneuploidy cases, 8 other autosome aneuploidy cases, 3 large cryptic genomic rearrangements, and 1 small supernumerary marker chromosome. Discrepancy between karyotype analysis and CMA was observed in 33 (44%, 33/75) mosaicisms involving 15 sex chromosomal abnormalities, 1 routine autosomal aneuploidies, 5 other autosome aneuploidy cases, 8 large cryptic genomic rearrangements, and 4 small supernumerary marker chromosomes. CONCLUSION: Considering the disparities between methods as well as the cell populations analyzed, both CMA and karyotype analysis have their own advantages and disadvantages. Therefore, CMA should ideally be used in combination with karyotyping to detect more cases of mosaicism than using either test alone.

Application of the prenatal BACs-on-Beads™ assay for rapid prenatal detection of sex chromosome mosaicism.

The prenatal BACs-on-Beads™ (BoBs) assay was introduced for rapid detection of abnormalities of chromosomes 13, 18, 21, X, and Y and specific nine significant microdeletion syndromes. The ability of prenatal BoBs to detect mosaicism ranged from 20 to 40%. However, there have been no prenatal studies of sex chromosome mosaicism in prenatal BoBs. Therefore, the present study was performed with an aim to uncover the detection level of sex chromosome mosaicism that application of prenatal BoBs assay, and then to assess the sensitivity of prenatal BoBs assay, thereby improving the prenatal diagnostic accuracy. A total of 31 samples of amniotic fluid (AF) and umbilical cord blood (UCB) for prenatal diagnosis were collected, and the results were confirmed through karyotyping, single nucleotide polymorphism microarray (SNP-array) and copy number variation sequencing (CNV-seq). 23 cases of sex chromosome mosaicism were prompted abnormal by prenatal BoBs, the minimum detection level of mosaicism was about 6% as detected by karyotype. The overall sensitivity of prenatal BoBs in the detection of sex chromosome mosaicism was 74.2% (23/31). This study evaluated the effectiveness of prenatal BoBs for detecting sex chromosome mosaicism in prenatal diagnosis, and the results will provide valuable information for genetic counseling.

Fetal growth restriction: associated genetic etiology and pregnancy outcomes in a tertiary referral center.

BACKGROUND: The etiology of fetal growth restriction (FGR) is complex and currently, there is a paucity of research about the genetic etiology of fetal growth restriction. We investigated the genetic associations and pregnancy outcomes in cases of fetal growth restriction. METHODS: A retrospective analysis of 210 pregnant women with fetal growth restriction was performed using karyotype analysis and single nucleotide polymorphism arrays (SNP-array). The differences in pathogenic copy number variation (CNV) detected by the two methods were compared. At the same time, the fetuses were divided into three groups: isolated FGR (n = 117), FGR with ultrasonographic soft markers (n = 48), and FGR with ultrasonographic structural anomalies (n = 45). Further, the differences in pathogenic copy number variations were compared among the groups. RESULTS: The total detection rate of pathogenic CNVs was 12.4% (26/210). Pathogenic copy number variation was detected in 14 cases (6.7%, 14/210) by karyotype analysis. Furthermore, 25 cases (11.9%, 25/210) with pathogenic CNVs were detected using the SNP-array evaluation method. The difference in the pathogenic CNV detection rate between the two methods was statistically significant. The result of the karyotype analysis and SNP-array evaluation was inconsistent for 13 cases with pathogenic CNV. The rate of detecting pathogenic CNVs in fetuses with isolated FGR, FGR combined with ultrasonographic soft markers, and FGR combined with ultrasonographic structural malformations was 6.0, 10.4, and 31.1%, respectively, with significant differences among the groups. During the follow-up, 35 pregnancies were terminated, two abortions occurred, and 13 cases were lost to follow-up. Of the 160 deliveries, nine fetuses had adverse pregnancy outcomes, and the remaining 151 had normal postnatal growth and developmental assessments. CONCLUSIONS: Early diagnosis and timely genomic testing for fetal growth restriction can aid in its perinatal prognosis and subsequent intervention.

Prenatal diagnosis of fetuses with region of homozygosity detected by single nucleotide polymorphism array: a retrospective cohort study.

Region of homozygosity (ROH) is classified as uniparental disomy (UPD) or identity by descent, depending on its origin. To explore the clinical relevance of ROH in prenatal diagnoses, we reviewed 5063 fetal samples subjected to single nucleotide polymorphism array at our center over 5 years. ROH cases meeting our reporting threshold were further analyzed. ROHs were detected in 22 fetuses (0.43%, 22/5063), of which, 77.3% (17/22) showed a ROH on a single chromosome and 22.7% (5/22) showed multiple ROHs on different chromosomes. Among 5063 fetuses undergoing invasive prenatal diagnoses owing to various indications, five cases were identified as UPDs with a rate of ~1/1000. We observed clinically relevant UPDs in two cases related to Prader-Willi syndrome and transient neonatal diabetes mellitus. Of note, one case showed 50% mosaicism for trisomy 2 in amniotic fluid, whereas a complete UPD (2) was observed in umbilical cord blood. Trio whole-exome sequencing was performed for three cases. Clinically relevant variants were identified in two cases, one of which, NM_000302:c.2071_2072insCC (p.R693Qfs*122) in PLOD1 located in the ROH, may be related to Ehlers-Danlos syndrome, kyphoscoliotic type, 1. Overall, 72.7% (16/22) of the ROH carriers showed ultrasound abnormalities, of whom eight (50%, 8/16) had adverse perinatal outcomes. Our study demonstrates that the clinical relevance of ROHs should be examined regarding fetuses with ROHs occurring on imprinted chromosomes or those derived from consanguineous parents in prenatal diagnoses; imprinting disorders and/or autosomal recessive diseases attributed to ROHs should be considered during genetic counseling.

Positive predictive value of noninvasive prenatal testing for sex chromosome abnormalities.

BACKGROUND: Early and intermediate serological screening cannot detect sex chromosome abnormalities. Currently, noninvasive prenatal testing (NIPT) is the only procedure available for screening such disorders; however, its use is controversial. METHODS AND RESULTS: A total of 47,855 pregnant women underwent NIPT at our referral center from January 2014 to December 2020. Of the 314 patients with a positive NIPT indicating sex chromosome abnormalities, 260 were screened via karyotype analysis and single nucleotide polymorphism (SNP) array after amniotic fluid extraction; 96 cases were confirmed. Karyotype analysis and SNP array were consistent in the diagnosis of 88 out of the 96 fetuses. The positive predictive value (PPV) for sex chromosome abnormalities was found to be 36.9%. The PPV in patients aged 30-34 years was significantly higher than that in patients aged < 30 years. No statistically significant difference was observed on the PPV among patients with or without previous adverse pregnancy outcomes. Moreover, 83 women carrying fetuses were diagnosed with a sex chromosome abnormality terminated their pregnancy. CONCLUSIONS: Improvements in detection and analytical technologies are needed to increase the accuracy of sex chromosome abnormalities detection. Pregnant women with a positive NIPT for these abnormalities may require invasive diagnostic procedures such as karyotype analysis and SNP array for better genetic counseling.

Characterization of phenylalanine hydroxylase gene variants and analysis of genotype-phenotype correlation in patients with phenylalanine hydroxylase deficiency from Fujian Province, Southeastern China.

BACKGROUND: Phenylalanine hydroxylase deficiency (PAHD) is the most prevalent inherited disorder of amino acid metabolism in China. Its complex phenotype includes many variants and genotypes among different populations. METHODS AND RESULTS: In this study, we analyzed the phenylalanine hydroxylase gene (PAH) variants in a cohort of 93 PAHD patients from Fujian Province. We also assessed genotype and phenotype correlation in patients with PAHD. A total of 44 different pathogenic variants were identified, including five novel variants. The three most prevalent variants among all patents were c.158G > A, p.(Arg53His) (18.03%), c.721C > T, p.(Arg241Cys) (14.75%), and c.728G > A, p.(Arg243Gln) (7.65%). The frequency of the c.158G > A, p.(Arg53His) variant was highest in patients with mild hyperphenylalaninemia, whereas the frequency of the c.1197A > T, p.(Val399 =) and c.331C > T, p.(Arg111Ter) variants was highest in patients with classic phenylketonuria. The most abundant genotypes observed in PAHD patients were c.[158G > A];[728G > A], c.[158G > A];[442-1G > A], and c.[158G > A];[721C > T]. Comparing allelic phenotype to genotypic phenotype values yielded fairly accurate predictions of phenotype, with an overall consistency rate was 85.71% for PAHD patients. CONCLUSIONS: Our study identified a PAH variant spectrum in PAHD patients from Fujian Province, Southeastern China. Quantitative correlation analysis between genotype and phenotype severity is helpful for genetic counseling and management.