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Thrombosis Journal Oct 2023Hemophilia A (HEMA) is an X-linked bleeding disorder caused by reduced/absent coagulation factor VIII expression, as a result of pathogenic variants in the F8 gene....
Robust preimplantation genetic testing of the common F8 Inv22 pathogenic variant of severe hemophilia A using a highly polymorphic multi-marker panel encompassing the paracentric inversion.
BACKGROUND
Hemophilia A (HEMA) is an X-linked bleeding disorder caused by reduced/absent coagulation factor VIII expression, as a result of pathogenic variants in the F8 gene. Preimplantation prevention of HEMA should ideally include direct pathogenic F8 variant detection, complemented by linkage analysis of flanking markers to identify the high-risk F8 allele. Linkage analysis is particularly indispensable when the pathogenic variant cannot be detected directly or identified. This study evaluated the suitability of a panel of F8 intragenic and extragenic short tandem repeat markers for standalone linkage-based preimplantation genetic testing for monogenic disorder (PGT-M) of the Inv22 pathogenic variant, an almost 600 kb paracentric inversion responsible for almost half of all severe HEMA globally, for which direct detection is challenging.
METHODS
Thirteen markers spanning 1 Mb and encompassing both F8 and the Inv22 inversion interval were genotyped in 153 unrelated females of Viet Kinh ethnicity.
RESULTS
All individuals were heterozygous for ≥ 1 marker, ~ 90% were heterozygous for ≥ 1 of the five F8 intragenic markers, and almost 98% were heterozygous for ≥ 1 upstream (telomeric) and ≥ 1 downstream (centromeric) markers. A prospective PGT-M couple at risk of transmitting F8 Inv22 were fully informative at four marker loci (2 intra-inversion, 1 centromeric, 1 telomeric) and partially informative at another five (2 intra-inversion, 3 centromeric), allowing robust phasing of low- and high-risk haplotypes. In vitro fertilization produced three embryos, all of which clearly inherited the low-risk maternal allele, enabling reliable unaffected diagnoses. A single embryo transfer produced a clinical pregnancy, which was confirmed as unaffected by amniocentesis and long-range PCR, and a healthy baby girl was delivered at term.
CONCLUSION
Robust and reliable PGT-M of HEMA, including the common F8 Inv22 pathogenic variant, can be achieved with sufficient informative intragenic and flanking markers.
PubMed: 37864173
DOI: 10.1186/s12959-023-00552-w -
Reproductive Sciences (Thousand Oaks,... Mar 2024Robertsonian translocations (ROBs) are the most common structural chromosomal abnormalities in the general population, with an estimated incidence rate of 1/1000 births....
Robertsonian translocations (ROBs) are the most common structural chromosomal abnormalities in the general population, with an estimated incidence rate of 1/1000 births. In this study, we retrospectively analyzed the cases of ROBs from September 2015 to August 2022 and totally identified ROB carriers from 84,569 specimens karyotyped in a single accredited laboratory in China, including 189 cases of balanced ROBs and 3 of mosaic ROBs. Microsoft Excel and descriptive statistics were used to record and analyze the collected data. The male/female ratio of ROBs is 1/1.29, with der(13;14) and der(14;21) being the main karyotypes. Among the 192 patients, 7 were lost to follow-up, 82 had given birth, and 103 were childless (such as miscarriage, fetal chromosomal abnormalities, in vitro fertilization (IVF) failure, or divorce). A total of 44 amniocenteses were performed in 42 couples; ROB cases with natural pregnancies showed that the normal karyotype and balanced ROBs of fetal accounted for 66.67% (16/24), while the results of assisted pregnancies showed 90.00% (18/20). This study represents the largest collections of ROBs in Jiangxi population and reminder that the ROB carriers can achieve the ideal outcome for pregnancy with the appropriate genetic guidance and assisted reproductive technologies (ART).
Topics: Pregnancy; Humans; Male; Female; Retrospective Studies; Translocation, Genetic; Chromosome Aberrations; Chromosome Disorders; Abortion, Spontaneous
PubMed: 37932552
DOI: 10.1007/s43032-023-01398-3 -
Cureus Jan 2024The cytomegalovirus (CMV), a common DNA virus with a high global seroprevalence, is the primary cause of teratogenic congenital infections, which presents a serious risk...
The cytomegalovirus (CMV), a common DNA virus with a high global seroprevalence, is the primary cause of teratogenic congenital infections, which presents a serious risk to public health. Maternal CMV infection is linked to congenital CMV (cCMV), a major contributor to non-genetic sensorineural hearing loss, cognitive developmental impairments, and cerebral palsy in infants. Transmission might occur through direct contact with infected bodily fluids, with higher transmission rates after primary infection and an increased risk of severe fetal effects before 20 weeks. The mother and fetus do not get immunity from a prior infection. Fetal growth restriction, fetal loss, and cerebral or extra-cerebral abnormalities that can be detected by ultrasonography are possible presentations of cCMV. Specific antibody detection or seroconversion is required for the diagnosis of maternal CMV during pregnancy. Amniocentesis is used to diagnose fetal CMV during pregnancy after eight weeks of presumed maternal infection and 17 weeks of gestation. The main preventive measure is hygiene education, as the effectiveness of immunoglobulins, antiviral medications, and vaccines is still up for debate. The focus is particularly directed toward the anomalous fetal outcomes observed during the course of the pregnancy.
PubMed: 38304637
DOI: 10.7759/cureus.51534 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Dec 2023Objective To explore the clinical significance of non-invasive prenatal testing(NIPT)for fetal chromosomal abnormalities in the cases of twin pregnancy and its...
Objective To explore the clinical significance of non-invasive prenatal testing(NIPT)for fetal chromosomal abnormalities in the cases of twin pregnancy and its relationship with age and other related factors.Methods A total of 3733 women with twin pregnancy of 12-26 weeks who voluntarily underwent NIPT in the Ningbo Women and Children's Hospital from January 2018 to December 2022 were selected.The results of NIPT and amniocentesis were compared and all the participants were followed up.The detection rate of chromosomal abnormalities by NIPT was calculated,and its correlations with age,gestational weeks,chorionicity,and pregnancy type were analyzed.Results Among the 3733 cases,71 cases of fetal chromosome abnormality were indicated by NIPT,including 13 cases of trisomy 21,19 cases of trisomy 18,5 cases of trisomy 13,18 cases of sex chromosome abnormality,and 16 cases of chromosome microdeletion/duplication(excluding 21,18,13,and sex chromosomes),among which 34 cases were true positive and 37 cases were false positive.The overall sensitivity,specificity,and positive predictive value(PPV)of NIPT for chromosomal abnormalities in the cases of twin pregnancy were 100%,98.99%,and 47.89%(34/71),respectively.NIPT showed the sensitivity,specificity,and PPV of 100%,99.78%,and 78.38%(29/37)for trisomy 21,18,and 13,100%,99.56%,and 16.67%(3/18)for sex chromosome abnormalities,and 100%,99.62%,and 12.5%(2/16)for chromosome microdeletion/duplication,respectively.In the age group of ≥40 years,the NIPT for chromosomal abnormalities showed the PPV of 66.67%,the sensitivity of 100%,and the misdiagnosis rate of 30%。However,the NIPT for trisomy 21,18,and 13 showed the PPV of 100%,the misdiagnosis rate of 0,and the sensitivity and specificity of 100%.In terms of grouping based on gestational weeks,the NIPT for chromosomal abnormalities showed the highest PPV(51.28%)in the women with twin pregnancy for 14-17 weeks,followed by that(50.00%)in the women with twin pregnancy for 22-26 weeks;the NIPT for trisomy 21,18,and 13 showed the highest PPV of 94.74% in the gestation group of 14-17 weeks,followed by that(83.33%)in the gestation group of 18-21 weeks.The rate of dichorionic diamniotic twins was higher in assisted pregnancies than in natural pregnancies,and NIPT showed the same detection efficiency for dichorionic diamniotic twins and monochorionic diamniotic twins and the same detection efficiency for different pregnancy types.Conclusions NIPT has high accuracy in the diagnosis of twin pregnancy and high sensitivity and high specificity for different ages and gestational weeks,especially for trisomy 21,18,and 13.NIPT is suitable for assisted pregnancy and natural pregnancy,and it is of high value in clinical application.However,extensive application needs a large population-based study.
Topics: Pregnancy; Child; Female; Humans; Adult; Down Syndrome; Pregnancy, Twin; Prenatal Diagnosis; Trisomy; Chromosome Aberrations
PubMed: 38173101
DOI: 10.3881/j.issn.1000-503X.15704 -
Molecular Genetics & Genomic Medicine Sep 2023To explore and compare the clinical effects of high-resolution non-invasive prenatal screening (NIPS-Plus) for common/uncommon chromosomal aneuploidy and...
BACKGROUND
To explore and compare the clinical effects of high-resolution non-invasive prenatal screening (NIPS-Plus) for common/uncommon chromosomal aneuploidy and microdeletion/microduplication syndromes (MMS).
METHODS
The current prospective study included a total of 25,380 pregnant women who performed NIPS-Plus, and amniocentesis was performed on women with MMS with the screening results to diagnose patients with suspected MMS.
RESULTS
There were 415 samples with positive results for NIPS-Plus, included 275 with aneuploidy and 140 with MMS. After diagnosis by amniocentesis, 188 cases were confirmed as true positive, included46 cases of T21, 9 cases of T18, 1 case of T13, 34 cases of SCA, 41 cases of other chromosomal euploidy and 57 cases of MMS. In addition, no false negative cases were found, MMS was classified with 5 Mb with the cutoff value, and the PPV of different fragment size was counted, respectively.
CONCLUSION
We found that the corresponding PPV was 44.66% with the fragment of copy number variation (CNV) being less than or equal to 5 Mb, and when it was greater than 5 Mb, the PPV was 29.73%, which suggested that NIPS-Plus was more suitable for screening the PPV of small fragment abnormalities. NIPS-Plus has a good application effect in routine aneuploidy screening and had the best detection effect for T21; moreover, it performed well in screening of MMS and had better detection effect on MMS with CNV fragment length less than 5 Mb. Based on the current results, we suggested that NIPS-Plus should be used as a comprehensive elementary prenatal screening method for all pregnant women, but for MMS caused by abnormal large fragment CNV, the detection method and efficiency still need to be improved.
Topics: Female; Humans; Pregnancy; DNA Copy Number Variations; Prospective Studies; Aneuploidy; Prenatal Diagnosis; Amniocentesis
PubMed: 37354111
DOI: 10.1002/mgg3.2200 -
European Journal of Obstetrics &... Mar 2024We aimed to examine amniotic fluid neutrophil gelatinase-associated lipocalin (NGAL) and L-type fatty acid-binding protein (L-FABP) levels during pregnancy.
OBJECTIVE
We aimed to examine amniotic fluid neutrophil gelatinase-associated lipocalin (NGAL) and L-type fatty acid-binding protein (L-FABP) levels during pregnancy.
STUDY DESIGN
This study included singleton pregnancies. Amniotic fluid samples were collected at the time of vaginal delivery, cesarean section, amniocentesis, amnioreduction, and amnioinfusion. We analyzed changes of the NGAL and L-FABP levels during pregnancy and the factors affecting these values and their association with clinical outcomes.
RESULTS
Three hundred and one pregnancies were analyzed. Respective Pearson correlation coefficients for the NGAL and L-FABP levels and gestational age at inspection were - 0.351 and - 0.819 (p <0.001 and p < 0.001, respectively); weak and strong negative correlation were observed. The NGAL level was significantly higher in the intra-amniotic infection group than in the control group (p < 0.001). The L-FABP level was significantly higher in the fetal blood flow abnormalities group than in the control group (p < 0.001). The NGAL and L-FABP levels were significantly higher in the adverse outcomes group than in the control group (p = 0.019 and p < 0.001, respectively), and the respective areas under the concentration-time curve, with optimal cutoff values, for the NGAL and L-FABP levels were 0.693 (14,800 µg/gCr) and 0.864 (378 µg/gCr).
CONCLUSIONS
Amniotic fluid NGAL and L-FABP levels reflect fetal and neonatal immaturity. Additionally, the NGAL level is a useful predictive factor of intra-amniotic infection, and the L-FABP level is a useful predictive factor of fetal condition and short- and long-term prognoses.
PubMed: 38125710
DOI: 10.1016/j.eurox.2023.100269 -
Heliyon Nov 2023Charcot-Marie-Tooth type 1A (CMT1A), the most frequent type of Charcot-Marie-Tooth disease, is mainly caused by a 1.4-Mb duplication containing the gene. There is no...
BACKGROUND
Charcot-Marie-Tooth type 1A (CMT1A), the most frequent type of Charcot-Marie-Tooth disease, is mainly caused by a 1.4-Mb duplication containing the gene. There is no effective treatment other than general supportive care and symptomatic treatment. Preimplantation genetic testing for monogenic defects (PGT-M) is an alternative approach for obtaining healthy babies.
METHODS
A new technology and analysis method based on next-generation sequencing (NGS) was developed to detect duplication mutations directly. Simultaneously, aneuploidy and linkage analyses were performed to achieve a comprehensive and accurate embryo diagnosis.
RESULTS
Eight couples were recruited in this study; duplication was validated in seven couples, and splicing mutation was found in one. Forty-five embryos from 12 PGT cycles were successfully detected using this novel method. The direct detection results for all embryos were consistent with the linkage analyses, suggesting a 100 % accuracy rate, and the aneuploidy rate of the biopsied blastocysts was 33.3 %. Eventually, 18 of the 45 diagnosed embryos were deemed suitable for transfer. Four healthy babies from three families were delivered and their genetic status confirmed by amniocentesis. Additionally, there were no adverse effects of anesthesia or increased pregnancy complications during PGT-M in female patients with CMT1A.
CONCLUSIONS
This study provided a simple, reliable, and efficient method that can directly detect mutations based on NGS data and does not require positive family members. A clinical workflow for CMT1A interruption in the offspring before embryo implantation is also summarized.
PubMed: 38045147
DOI: 10.1016/j.heliyon.2023.e22196 -
Taiwanese Journal of Obstetrics &... Jan 2024We present prenatal diagnosis and perinatal findings of 17q12 microdeletion encompassing HNF1B in a fetus with bilateral hyperechogenic kidneys on fetal ultrasound and... (Review)
Review
Prenatal diagnosis and perinatal findings of 17q12 microdeletion encompassing HNF1B in a fetus with bilateral hyperechogenic kidneys on fetal ultrasound and mild renal abnormality after birth, and a review of the literature of prenatal diagnosis of 17q12 microdeletion.
OBJECTIVE
We present prenatal diagnosis and perinatal findings of 17q12 microdeletion encompassing HNF1B in a fetus with bilateral hyperechogenic kidneys on fetal ultrasound and mild renal abnormality after birth, and a review of the literature.
CASE REPORT
A 36-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes showed a de novo 1.38-Mb 17q12 microdeletion encompassing LHX1 and HNF1B. The parents did not have such a microdeletion. Prenatal ultrasound showed bilateral hyperechogenic kidneys with normal corticomedullary (CM) differentiation. The parents elected to continue the pregnancy, and a grossly normal 3180-g male baby was delivered at 39 weeks of gestation. aCGH analysis on the cord blood DNA revealed arr [GRCh37 (hg19)] 17q12 (34,856,055-36,248,918) × 1.0 with a 1.393-Mb microdeletion encompassing the genes of MYO19, PIGW, GGNBP2, DHRS11, MRM1, LHX1, AATF, ACACA, TADA2A, DUSP14, SYNRG, DDX52 and HNF1B. When follow-up at age 2 years and 4 months, the renal ultrasound revealed bilateral increased renal echogenicity with normal CM differentiation and small left renal cysts. The blood test revealed BUN = 28 mg/dL (normal: 5-18 mg/dL) and creatinine = 0.5 mg/dL (normal: 0.2-0.4 mg/dL).
CONCLUSION
17q12 microdeletion encompassing LHX1 and HNF1B at prenatal diagnosis may present variable clinical spectrum with bilateral hyperechogenic kidneys on fetal ultrasound and mild renal abnormality after birth. Prenatal diagnosis of fetal hyperechogenic kidneys should raise a suspicion of 17q12 microdeletion syndrome.
Topics: Adult; Child, Preschool; Female; Humans; Male; Pregnancy; 17-Hydroxysteroid Dehydrogenases; Amniocentesis; Apoptosis Regulatory Proteins; Chromosome Deletion; Comparative Genomic Hybridization; DNA; Fetus; Hepatocyte Nuclear Factor 1-beta; Kidney; Prenatal Diagnosis; Repressor Proteins; Ultrasonography, Prenatal; Urogenital Abnormalities
PubMed: 38216274
DOI: 10.1016/j.tjog.2023.10.005 -
AJOG Global Reports May 2024Preterm birth accounts for 60% to 80% of neonatal mortality. Approximately one-third of preterm births are caused by the spontaneous onset of preterm labor....
BACKGROUND
Preterm birth accounts for 60% to 80% of neonatal mortality. Approximately one-third of preterm births are caused by the spontaneous onset of preterm labor. Nevertheless, 70% to 90% of women diagnosed with preterm labor will not deliver within 7 days. Thus, many women will be unnecessarily treated by preterm labor with risk medications. Better tools are needed to categorize women in preterm labor into high or low risk of preterm delivery.
OBJECTIVE
This study aimed to evaluate the amino-terminal pro-brain natriuretic peptide concentration in the amniotic fluid as a prognostic test to predict the risk of delivery within 48 hours or 7 days and before 34 0/7 or 37 0/7 weeks of gestation in women in preterm labor.
STUDY DESIGN
A total of 102 pregnant women presenting signs and symptoms of spontaneous preterm birth (22 0/7 to 34 0/7 weeks of gestation) were included. Amniotic fluid was obtained by amniocentesis, and amino-terminal pro-brain natriuretic peptide concentration was measured. Below normal concentration was defined as <0.5 multiples of the median of the standard curve according to gestational age. The risk of preterm delivery was estimated according to normal or lower-than-normal amino-terminal pro-brain natriuretic peptide concentrations. The predictive capacity of the test (below normal amino-terminal pro-brain natriuretic peptide concentration) was evaluated to identify spontaneous preterm birth at 48 hours or 7 days from amniocentesis and less than 34 0/7 or 37 0/7 weeks at delivery.
RESULTS
For the outcome delivery within 48 hours, lower-than-normal amino-terminal pro-brain natriuretic peptide concentration had 94.6% sensitivity, 73.8% specificity, 96.0% negative predictive value, 3.61 positive likelihood ratio, and 0.07 negative likelihood ratio. For the outcome delivery within 7 days, the test had 93.9% sensitivity, 88.7% specificity, 94.0% negative predictive value, 8.31 positive likelihood ratio, and 0.07 negative likelihood ratio. For the outcomes of spontaneous preterm birth before 34 0/7 and 37 0/7 weeks of gestation, below normal amino-terminal pro-brain natriuretic peptide concentrations had 80.0% sensitivity, 83.0% specificity, 78.0% negative predictive value, 4.70 positive likelihood ratio, and 0.24 negative likelihood ratio and 64.1% sensitivity, 91.7% specificity, 44.0% negative predictive value, 7.70 positive likelihood ratio, and 0.39 negative likelihood ratio, respectively.
CONCLUSION
Among patients in spontaneous preterm labor, the detection of lower-than-normal amino-terminal pro-brain natriuretic peptide concentrations (<0.5 multiples of the median) in amniotic fluid has an excellent predictive capacity to identify those patients at low risk of preterm delivery within 48 hours or 7 days.
PubMed: 38681954
DOI: 10.1016/j.xagr.2024.100345 -
Taiwanese Journal of Obstetrics &... Nov 2023We present high-level mosaic trisomy 21 at amniocentesis in a pregnancy associated with positive non-invasive prenatal testing (NIPT) for trisomy 21, prenatal...
High-level mosaic trisomy 21 at amniocentesis in a pregnancy associated with positive NIPT for trisomy 21, prenatal progressive decrease of the trisomy 21 cell line, acute fatty liver of pregnancy and intrauterine fetal death in late gestation.
OBJECTIVE
We present high-level mosaic trisomy 21 at amniocentesis in a pregnancy associated with positive non-invasive prenatal testing (NIPT) for trisomy 21, prenatal progressive decrease of the trisomy 21 cell line, acute fatty liver of pregnancy and intrauterine fetal death (IUFD) in late gestation.
CASE REPORT
A 32-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of positive NIPT for trisomy 21 at 12 weeks of gestation. This pregnancy was conceived by in vitro fertilization. She did not have obesity, diabetes mellitus, hepatic biliary disorders and preeclampsia. Amniocentesis revealed a karyotype of 47,XY,+21[10]/46,XY[11], and array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed the result of arr (21) × 2-3. She was referred for genetic counseling, and repeat amniocentesis performed at 21 weeks of gestation revealed the karyotype of 47,XY,+21[10]/46,XY[28]. The parental karyotypes and fetal ultrasound findings were normal. Simultaneous molecular analysis on uncultured amniocytes showed no uniparental disomy 21, but a maternal origin of trisomy 21 by quantitative fluorescent polymerase chain reaction (QF-PCR) and the result of arr 21q11.2q22.3 × 2.5 by aCGH analysis. At 27 weeks of gestation, she underwent a third amniocentesis, of which conventional cytogenetic analysis revealed the result of 47,XY,+21[5]/46,XY[17] in cultured amniocytes, and aCGH analysis revealed arr 21q11.2q22.3 × 2.48, and interphase fluorescence in situ hybridization (FISH) analysis revealed 39% (39/100 cells) mosaicism fro trisomy 21 in uncultured amniocytes. At 36 weeks of gestation, the woman suffered from a sudden onset of acute fatty liver and IUFD. A 3522-g male baby was delivered without Down syndrome phenotype. The umbilical cord had a karyotype of 47,XY,+21[10]/46,XY[30]. aCGH analysis on the skin and placenta showed arr 21q11.2q22.3 × 2.73 and arr 21q11.2q22.3 × 2.75, respectively. QF-PCR analysis of umbilical cord, placenta and skin showed a maternal origin of trisomy 21.
CONCLUSION
High-level mosaic trisomy 21 at amniocentesis can be associated with prenatal progressive decrease of the trisomy 21 cell line in cultured amniocytes and perinatal fetal mortality and maternal morbidity.
Topics: Female; Pregnancy; Male; Humans; Adult; Amniocentesis; Down Syndrome; Mosaicism; In Situ Hybridization, Fluorescence; Comparative Genomic Hybridization; Trisomy; Fatty Liver; Stillbirth; Cell Line
PubMed: 38008511
DOI: 10.1016/j.tjog.2023.09.003