OBJECTIVE: To investigate the genetic mechanism for adverse pregnancies due to submicroscopic chromosomal structural variants in two cases, and to provide a precise guidance for preimplantation genetic testing. METHODS: Two families who had visited Chengdu Women's and Children's Central Hospital for reproduction guidance due to recurrent miscarriages, adverse pregnancy history and abnormal genetic testing of the offspring in June and December 2023 were selected as the study subjects. Chromosomal karyotyping and optical genome mapping (OGM) were carried out on peripheral blood samples from the two couples, and preimplantation genetic testing for structural rearrangement (PGT-SR) were performed on the blastocyst trophoblasts. This study was approved by the Medical Ethics Committee of the Hospital (Ethic No.: 2023-23). RESULTS: No abnormality was found on the G-banded karyotyping analysis for both couples. The OGM results revealed that the female partner of couple 1 had a translocation between 4pter-p16.3 (3.99 Mb) and 11pter-p15.4 (2.66 Mb), whilst no abnormality was found in the male partner. Similarly, the male partner of couple 2 had a translocation between 19q13.43-qter (1.90 Mb) and 22q13.31-qter (3.34 Mb). No abnormality was found in the female partner of couple 2. Neither breakpoints nor the adjacent region had involved an OMIM gene, except the formation of a fusion gene ZIM2-AS1-Z82186.1 (Both genes are non-coding, and the fusion gene was deemed as variant of unknown significance). PGT-SR of 11 blastocysts derived from couple 1 revealed that one embryo was suitable for priority transfer, three embryos were suitable for transfer, one embryo was recommended for genetic counselling, and six embryos were unsuitable for the transfer. For couple 2, six blastocysts were tested, of which only one embryo was deemed suitable for transfer. CONCLUSION When genetic testing of offspring indicates copy number variations such as deletions, duplications or mosaicism, the high-resolution OGM technique can be selected to screen parents for submicroscopic chromosomal structural variations. The result can facilitate accurate assessment for the risk of recurrence in offspring, selection of suitable method for reproduction, and identifying targets for PGT.
Humans ; Female ; Pregnancy ; Adult ; Male ; Karyotyping ; Chromosome Aberrations ; Abortion, Habitual/genetics* ; Preimplantation Diagnosis ; Genetic Testing

OBJECTIVES: Chromosomal abnormalities are the most common cause of spontaneous abortion (SA). This study aims to analyze the association between SA and chromosomal abnormalities in products of conception, and to compare the impact of different pregnancy modes and different numbers of previous abortions on chromosomal abnormalities, providing clinical consulting references. METHODS: A total of 1 345 SA patients treated at the Affiliated Women's Hospital of Jiangnan University (Wuxi Maternity and Child Health Care Hospital) between January 2019 and December 2023 were enrolled. According to the mode of conception, patients were divided into 2 groups: a spontaneous pregnancy group (S group, n=1242) and an assisted reproductive technology (ART)-conceived group (ART group, n=103). Based on the number of miscarriages, the S group was further subdivided into a spontaneous sporadic abortion group (S-1 group, n=780) and a spontaneous recurrent abortion group (S-2 group, n=462); the ART group was subdivided into an ART sporadic abortion group (ART-1 group, n=68) and an ART recurrent abortion group (ART-2 group, n=35). Chromosomal microarray analysis (CMA) was performed on products of conception. RESULTS: The incidence of numerical chromosomal abnormalities was 56.79% (443/780) in the S-1 group and 52.38% (242/462) in the S-2 group, while the incidence of structural abnormalities was 4.36% (34/780) and 7.36% (34/462), respectively. There was a statistically significant difference in structural abnormalities between the 2 groups (P<0.05). Among the spontaneous pregnancy SA cases, the incidence of numerical abnormalities decreased with increasing numbers of miscarriages, and was significantly lower in the group with ≥4 miscarriages compared to those with 1 or 2 miscarriages (both P<0.05). The incidence of structural abnormalities in groups with 1, 2, 3, and ≥4 miscarriages was 3.46%, 5.65%, 5.88%, and 4.35%, respectively, with no statistically significant differences among groups (all P>0.05). The incidence of pathogenic copy number variants (pCNVs) plus likely pathogenic copy number variants (LP-CNVs) gradually increases in the group with 1-3 miscarriages, and there was a statistically significant difference between the group with 1 miscarriage and the group with 2 miscarriages (P<0.05). In the ART group, the incidence of numerical abnormalities was 47.06% (32/68) in ART-1 and 37.14% (13/35) in ART-2, while structural abnormalities occurred in 2.94% (2/68) and 11.43% (4/35), respectively, with no significant differences between the groups (both P>0.05). There were no statistically significant differences in the incidence of numerical or structural abnormalities between the S-1 and ART-1 groups, or between the S-2 and ART-2 groups (all P>0.05). CONCLUSIONS Chromosomal numerical and structural abnormalities are common in SA patients from both spontaneous and ART-conceived pregnancies. Attention should be paid to patients with recurrent miscarriage in genetic investigation.
Humans ; Female ; Pregnancy ; Chromosome Aberrations/statistics & numerical data* ; Abortion, Spontaneous/epidemiology* ; Adult ; Reproductive Techniques, Assisted/adverse effects* ; Abortion, Habitual/genetics* ; Fertilization

Multiple myeloma (MM) is a common hematologic malignancy that originates from precursor conditions such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Identifying its risk factors is crucial for early intervention. The etiology of MM is multifactorial, involving race, familial clustering, gender, age, obesity, cytogenetic abnormalities, and environmental exposures. Among these, cytogenetic abnormalities and modifiable factors play pivotal roles in MM pathogenesis and progression. 1) cytogenetic abnormalities. Primary abnormalities [e.g., hyperdiploidy, t(11;14), t(14;16)] emerge at the MGUS stage, while secondary abnormalities [e.g., 1q+, del(17p)] drive disease progression. The accumulation of 1q+ promotes clonal evolution, and del(17p) is associated with significantly reduced survival. 2) modifiable risk factors. Obesity promotes MM via the acetyl-CoA synthetase 2 (ACSS2)-interferon regulatory factor 4 (IRF4) pathway. Vitamin D deficiency weakens immune surveillance. Exposure to herbicides such as Agent Orange and glyphosate increases MGUS incidence. Insufficient UV exposure, by reducing vitamin D synthesis, elevates MM risk. Gut microbiota dysbiosis (enrichment of nitrogen-cycle bacteria and depletion of short-chain fatty acids producers) induces chromosomal instability through the ammonium ion-solute carrier family 12 member 22 (SLC12A2)-NEK2 axis. Therefore, risk-based screening among high-risk populations (e.g., those who are obese, elderly, or chemically exposed), along with early interventions targeting cytogenetic abnormalities [e.g., B cell lymphoma 2 (Bcl-2) inhibitors for t(11;14), ferroptosis inducers for t(4;14)] and modifiable factors (e.g., vitamin D supplementation, gut microbiota modulation), may effectively delay disease progression and improve prognosis.
Humans ; Multiple Myeloma/epidemiology* ; Risk Factors ; Obesity/complications* ; Chromosome Aberrations ; Monoclonal Gammopathy of Undetermined Significance/etiology* ; Gastrointestinal Microbiome ; Vitamin D Deficiency/complications* ; Precancerous Conditions/genetics*

OBJECTIVE: To analyze the chromosome status of pre-implantation embryos from women of different ages, and assess the impact of age on it. METHODS: A retrospective analysis was carried out on the results of PGT-A and PGT-M+PGT-A cycles by whole-genome amplification followed by next generation sequencing at the Second People's Hospital of Nanning between July 2021 and November 2023. The embryos were divided into five groups based on the women's age: ≤ 30 years old group, 31 ~ 34 years old group, 35 ~ 37 years old group, 38 ~ 40 years old group, and ≥ 41 years old group.The chromosomal status of embryos for each group was compared. This study has been approved by the Ethic Committee of the Hospital (Ethics No. Y2024312A). RESULTS: This study has involved 390 couples and 436 PGT cycles, with a total of 1 651 blastocysts biopsied and analyzed. Among these, 835 embryos (50.6%) were found to have chromosomal abnormalities, including 490 (29.7%) with aneuploidies, 154 (9.3%) with chromosomal segment abnormalities, and 264 (16.0%) with chromosome mosaicisms. After adjusting the dosages of Gn, female BMI, male age, PGT indications, infertility type, LH, AMH and other parameters, maternal age appeared to be an independent factor for chromosomal abnormalities and aneuploidies in blastocysts (OR = 1.132, 95%CI = 1.089-1.177, P < 0.001; OR = 1.250, 95%CI = 1.188-1.315, P < 0.001). With the increase in female age, embryonic chromosome abnormalities have significantly increased in each group, with the rates being 32.3% (126/390), 43.1% (189/439), 45.1% (116/257), 66.3% (250/377), and 81.9% (154/188) (P < 0.001). Chromosomal aneuploidies have also significantly increased, with the rates being 8.2% (32/390), 16.6% (73/439), 24.5% (63/257), 49.6% (187/377), and 71.8% (135/188) (P < 0.001). The proportion of embryos with ≥ 2 chromosome abnormalities also significantly increased in abnormal embryos, with the rates being 28.6% (36/126), 30.2% (57/189), 39.7% (46/116), 48.4% (121/250), and 64.9% (100/154) (P < 0.001). Of note, the female age did not affect the prevalence of chromosomal segment abnormalities and mosaicisms (all P > 0.05). CONCLUSION Above findings suggested that along with the increase in female age, there is an increase in the rate and complexity of chromosomal abnormalities, which may contribute to infertility in women with elder age.
Humans ; Female ; Maternal Age ; Adult ; Retrospective Studies ; Chromosome Aberrations ; Preimplantation Diagnosis/methods* ; Pregnancy ; Blastocyst/metabolism* ; Aneuploidy ; Fertilization in Vitro ; Male

OBJECTIVE: To analyze the results of prenatal diagnosis for fetuses with a high risk for sex chromosome aneuploidies (SCAs) indicated by non-invasive prenatal testing (NIPT), and to assess the influence of maternal chromosomal factors on the results of NIPT. METHODS: A retrospective analysis was conducted on the clinical data of 454 pregnant women with a high risk for SCAs indicated by NIPT undergoing invasive prenatal diagnosis at the Medical Genetics Center of Northwest Women's and Children's Hospital from January 2022 to September 2024. The data has included prenatal diagnosis indications, results, pregnancy outcomes, and the chromosomal results of pregnant women. RESULTS: Among the 454 women (including 10 with twin pregnancy) with a high risk for SCAs indicated by NIPT, 149 (including 4 twin cases) were diagnosed with SCAs through invasive prenatal diagnosis. These had included 47,XXX (37 cases), 47,XXY (56 cases), 47,XYY (29 cases), 45,X (1 case), 48,XXYY (1 case), mosaicism (20 cases), sex chromosome structural abnormalities (6 cases), and small-scale pathogenic copy number variations (3 cases). 383 pregnant women (including 7 with twin pregnancy) had accepted chromosomal karyotyping analysis. In total 49 cases of SCAs abnormalities were detected. Among them, 41 cases were pregnant women with SCAs but normal fetal chromosomes, which yielded a false positive rate for NIPT caused by maternal factors by 10.7%. In addition, 8 cases (including 1 twin case) had SCAs abnormalities in both the pregnant woman and the fetus. Among the 383 pregnant women, 129 cases (including 3 twin cases) of fetal SCAs were diagnosed, which yielded an overall positive predictive value (PPV) of NIPT for SCAs by 33.7% (129/383). With the 41 false positive cases caused by maternal SCAs abnormalities excluded, the PPV of NIPT for SCAs will be increased to 37.7% (129/342). Among the 454 pregnant women, twin pregnancies have accounted for 2.2% (10/454). Among the confirmed cases of SCAs abnormalities, twin cases accounted for 2.7% (4/149). Among the 383 pregnant women undergoing chromosomal karyotyping, twin cases accounted for 1.8% (7/383). Among the detected cases of chromosomal abnormalities, twin cases accounted for 2.0% (1/49). By calculation, the proportion of singleton pregnant women with a high risk for SCAs indicated by NIPT was approximately 32.1%, and the proportion of twin pregnant women was approximately 38.6%, indicating that twin pregnancies could increase the positive rate of NIPT. CONCLUSION NIPT can improve the screening efficiency for SCAs, but its PPV is limited. Therefore, pregnant women with a high risk for SCAs indicated by NIPT need to undergo invasive prenatal diagnosis for a definite diagnosis, and twin pregnancies can increase the positive rate of NIPT. The study confirmed that chromosomal abnormalities in pregnant women can significantly affect the accuracy of NIPT in detecting fetal SCAs. Therefore, when NIPT indicates SCAs abnormalities, it is recommended to simultaneously conduct chromosomal testing on the pregnant women. The combined application of chromosomal karyotyping analysis, fluorescence in situ hybridization, and copy number variation detection techniques can significantly improve the diagnostic accuracy for SCAs, especially for the detection of mosaicisms.
Humans ; Female ; Pregnancy ; Sex Chromosome Aberrations ; Adult ; Retrospective Studies ; False Positive Reactions ; Prenatal Diagnosis/methods* ; Noninvasive Prenatal Testing/methods* ; Aneuploidy ; Male ; Sex Chromosome Disorders/genetics*

OBJECTIVE: To analyze a patient with infertility due to complex chromosome rearrangement by optical genome mapping (OGM). METHODS: A female patient who was diagnosed with "primary infertility" at Shenzhen Longhua District Maternal and Child Health Care Hospital in April 2024 was selected as the study subject. Clinical data of the patient was collected. Chromosome G banding karyotyping analysis was carried out for the patient and her parents, in addition with OGM and copy number variation sequencing (CNV-seq). This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2023052504). RESULTS: The patient, a 33-year-old female, had infertility for the past 5 years. OGM revealed formation of two derivative chromosomes through rearrangement of chromosomes 5 and 18. A loss of heterozygosity on chromosome 5 was also detected by OGM and CNV-seq techniques. Both of her parents had a normal karyotype. CONCLUSION The OGM technique can refine the position of chromosomal breakpoints and determine the direction and position of insertional fragment. Combined with karyotype analysis, the OGM can accurately determine the chromosomal karyotype of the patient and facilitate genetic counseling.
Humans ; Female ; Adult ; Karyotyping ; DNA Copy Number Variations/genetics* ; Chromosome Mapping/methods* ; Chromosome Aberrations ; Infertility, Female/diagnosis*

OBJECTIVE: To apply optical genome mapping (OGM) technique for the analysis of genetic etiology in two rare families with complex chromosomal rearrangements (CCRs) and to provide precise reproductive guidance to them. METHODS: Two Chinese families diagnosed with chromosomal rearrangements by chromosomal microarray analysis (CMA) or whole-exome sequencing (WES) between June and December 2023 at the Affiliated Women and Children's Hospital of Ningbo University were selected as the study subjects. In both cases, unbalanced chromosomal translocations were suspected. Clinical data were collected, and peripheral blood from the couple, amniotic fluid sample and aborted fetal tissue was subjected to combined G-banding karyotyping and OGM for comprehensive genetic analysis. This study has been approved by the Medical Ethics Committee of the Hospital (Ethics No.: EC2023-094). RESULTS: In family 1, the fetus was signaled to have abnormal chromosome 7 by non-invasive prenatal testing (NIPT), prompting amniocentesis and CMA detection. In family 2, a pregnancy loss had occurred at 10 weeks' gestation, and trio-WES was carried out. Both fetuses were found to harbor copy number variations (CNVs) suggestive of unbalanced CCRs. Further analysis with OGM has revealed that, in family 1, an unbalanced rearrangement involving chromosomes 7, 8, and 10 was carried by the fetus and the pregnant woman, which has formed der(8) and der(10) derivative chromosomes. In family 2, a maternal CCR was found, which involved chromosomes 2 and 13 with seven breakpoints, resulting in unbalanced fetal CNVs. After genetic counseling, family 1 opted to continue with the pregnancy, considering the woman's normal appearance and inheritance of the rearrangement. For both families remained to have a risk for unbalanced rearrangements in subsequent pregnancies, preimplantation genetic testing (PGT) was recommended. CONCLUSION In both families, the OGM has precisely delineated the genetic basis of fetal CNVs and mapped the maternal CCR breakpoints, providing critical insights for genetic counseling and reproductive decision-making.
Adult ; Female ; Humans ; Male ; Pregnancy ; Chromosome Aberrations ; Chromosome Disorders/genetics* ; Chromosome Mapping/methods* ; Genetic Testing/methods* ; Pedigree ; Prenatal Diagnosis/methods* ; Translocation, Genetic

OBJECTIVE: To explore the mechanism and clinical manifestations of a case with complex structural variations involving chromosomes 5, 7, and 14, and assess the value of Chromosome conformation-based karyotyping (C-MoKa) for its diagnosis. METHODS: Two half-sibs by the same father presented at the First Hospital of Lanzhou University in December 2024 for severe multi-system abnormalities were selected as study subjects. Peripheral blood samples from the their parents were subjected to conventional chromosomal karyotyping analysis. The father was further analyzed using C-MoKa, while both siblings underwent copy number variation sequencing (CNV-seq). This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: LDYYSZLLKH2025-05). RESULTS: Conventional karyotype analysis indicated that the father has a karyotype of 46,XY,add(5)(p15.3). CNV-seq identified multiple chromosomal abnormalities in both siblings, including duplications and deletions of chromosomes 14 and 5. C-MoKa analysis further revealed a complex chromosomal structural variation involving chromosomes 5, 7, and 14 in the father. These variations were closely associated with the severe phenotypes noted in both children. CONCLUSION Complex chromosomal structural variations can lead to multi-system abnormalities and significantly impact reproductive health. Compared to conventional karyotyping, the C-MoKa technique has shown significant advantage in identifying such complex rearrangements. The combined application of multiple techniques can improve the accuracy of diagnosis, enabling genetic counseling for carriers to reduce their risk for producing further affected offspring.
Female ; Humans ; Male ; China ; Chromosome Aberrations ; DNA Copy Number Variations/genetics* ; Karyotyping ; Pedigree ; East Asian People/genetics*

OBJECTIVE: To assess the value of Optical genome mapping (OGM) for the verification of chromosomal structural variations among patients undergoing assisting reproduction. METHODS: A retrospective analysis was carried out on the clinical data of 12 patients presented at the Reproductive Center of Ningbo University Women and Children's Hospital from October 2022 to October 2024. All patients had undergone OGM testing due to suspection of structural variants by chromosomal karyotyping or a suggestive medical history. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: EC2024-148). RESULTS: Among the 12 patients verified by OGM, one (8.3%) was in keeping with the result of chromosomal karyotyping. Revised karyotypes were confirmed in seven cases (58.3%), including four with complex chromosomal rearrangements. Structural variation was excluded in three cases (25.0%). Of note, OGM has identified a previously undetected cryptic balanced translocation, i.e., ogm[GRCh38] t(7;12)(q36.3;q24.23)(157511190_157523142;119205703_119198409). CONCLUSION OGM can serve as an auxiliary diagnostic technique to conventional karyotyping and enable validation of suspected structural variations in those with ambiguous karyotype results or a history of adverse pregnancies. This can provide more precise genetic diagnosis for patients undergoing assisted reproduction and selection of clinical intervention strategies.
Humans ; Female ; Adult ; Retrospective Studies ; Karyotyping ; Reproductive Techniques, Assisted ; Chromosome Mapping/methods* ; Chromosome Aberrations

OBJECTIVE: To investigate the characteristics of chromosomal abnormalities in amniotic fluid among pregnant women in Liangshan Prefecture and explore strategies for optimizing prenatal diagnosis. METHODS: A retrospective analysis was conducted on 1 024 amniocentesis samples collected at the Prenatal Diagnosis Center of Liangshan Prefecture Maternal and Child Health Care Hospital between February 2022 and December 2024. Chromosome karyotyping analysis (3 cases had failed culture, 1 021 valid samples) was combined with high-throughput chromosome sequencing analysis (CNV-seq) for the detection. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 2023-07). RESULTS: The overall detection rate of chromosomal karyotype abnormalities in the amniotic fluid cells was 4.02% (41/1 021), with numerical abnormalities accounting for 80.49% (33/41) and structural abnormalities for 19.51% (8/41). Numerical abnormalities were primarily trisomy 21 (16/41, 39.02%) and 47,XXY (6/41, 14.63%). Structural abnormalities included translocations (6 cases) and mosaicism (2 cases). CNV-seq detected 22 pathogenic or likely pathogenic copy number variations, whilst the undetection rate for balanced translocations reached 100% (7/7). The combined application of karyotyping and CNV-seq, leveraging complementary strengths, can enhance the overall detection rate. CONCLUSION The distribution characteristics of chromosomal abnormalities in amniotic fluid from pregnant women in Liangshan exhibit regional specificity. A combined testing strategy significantly optimizes prenatal diagnosis efficacy, providing crucial evidence for enhancing the effectiveness of prenatal diagnosis in ethnic minority regions.
Humans ; Female ; Pregnancy ; Prenatal Diagnosis/methods* ; Chromosome Aberrations ; Retrospective Studies ; Adult ; Amniotic Fluid ; Karyotyping ; Amniocentesis ; Chromosome Disorders/genetics* ; China ; High-Throughput Nucleotide Sequencing ; DNA Copy Number Variations/genetics*