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At least 19 recordsLinked to original sources
PubMed2026

Genomic risk profiling in advanced maternal age: a Tamil Nadu prenatal study.

BACKGROUND: Advanced maternal age (AMA; > = 35 years) is associated with increased fetal chromosomal risk and is an important indication for invasive prenatal diagnosis. This study evaluates karyotyping and chromosomal microarray analysis (CMA) findings among AMA pregnancies in Tamil Nadu, India. METHODS: In this prospective observational study, 2,200 pregnant women aged ≥35 years who underwent amniocentesis between July 2020 and June 2021 were enrolled. Conventional karyotyping was performed in all cases. CMA was performed as a reflex or complementary test when predefined clinical or cytogenetic criteria were present, including ultrasound abnormalities, high-risk screening/NIPT results, abnormal or uncertain karyotype findings, prior adverse pregnancy history suggestive of genetic etiology, parental chromosomal abnormalities, or patient request after counseling. RESULTS: Numerical chromosomal abnormalities were detected in 76/2200 cases (3.5%), and structural abnormalities were detected in 9/2200 cases (0.4%). The total abnormal cytogenetic yield was therefore 85/2200 cases (3.9%) when numerical and structural abnormalities were considered together. Age-stratified analysis showed an increasing trend in chromosomal abnormalities with advancing maternal age, reaching 10.4% in women aged > = 43 years. Cases with additional clinical indications showed higher abnormality rates than simple AMA. CMA was performed in selected cases and contributed to characterization of clinically relevant genomic abnormalities, supporting its role in indicated high-risk AMA pregnancies. CONCLUSION: The Tamil Nadu cohort provides regional evidence on age-stratified cytogenetic risk in AMA pregnancies and supports the use of clearly defined criteria for integrating CMA with conventional karyotyping in prenatal diagnosis.

India↗
PubMed1977

An unexpected high frequency of trisomic fetuses in 229 pregnancies monitored for advanced maternal age.

In 229 pregnancies monitored because of advance maternal age, 16 (7%) abnormal fetal karyotypes were detected. We found 13 cases of trisomy 21, twice a trisomy 18, and once an additional marker chromosome. The frequency of abnormal fetal karyotypes in different maternal age groups was found to increase from 1:20 at 38--40 years, to 1:16 at 41--43 years, and finally to 1:4.5 in women of 44--46 years. The overall incidence of chromosomal aberrations and specifically of trisomy 21 is considerably higher than that described in retrospective studies.

Adult↗
PubMed1979

Reducing birth defect risk in advanced maternal age.

The incidence of birth defects increases with maternal age. Recent advances in fetal diagnosis, coupled with elective abortion, offer the older pregnant woman an opportunity to reduce this risk. To determine the magnitude of potential risk reduction, we reviewed the maternal age-specific incidence of infants born with one or more severe birth defects in metropolitan Atlanta from 1968 to 1975, removing from analysis certain anomalies that were preventable by currently available methods. For women aged 35 to 44 years, the risk of bearing an infant with a severe birth defect was reduced to a level comparable with that for younger women. Despite prenatal diagnosis and elective abortion, the risk for women aged 45 years or older, although reduced considerably, was two times greater than that for women aged 34 years or younger.

Adult↗
PubMed1978

[Prenatal diagnosis in pregnancies at advanced maternal age (author's transl)].

Among 113 prenatal diagnoses in pregnancies at advanced maternal age (mothers older than 37 years) 7 aberrant fetal karyotypes were found (6.2%). Detailed reports of one case of trisomy 21, 18 and 13 each, as well as of XXY-, XYY- and XXX gonosomal constitution respectively are presented in the following. The frequency and severity of chromosome aberrations occurring in fetuses from elder women are discussed with respect to data from the literature. It seems that this group bears a higher risk for chromosomally abnormal offspring than has been suggested before.

Abnormalities, Multiple↗
PubMed1975

Intrauterine diagnosis of chromosome anomalies.

Prenatal karyotype analysis was performed on cultured fetal cells obtained by transabdominal amniocentesis at the 15th and 20th week of pregnancy in 63 high risk pregnancies. The reason was advanced maternal age in 42 cases, a previous child with a chromosome anomaly in 13 cases, and parental balanced chromosome translocation in 7 cases. One mother was a haemophilia A carrier. Two mothers over 40 were found to be carrying a 21-trisomic fetus. In the group of parental balanced translocation one fetus showed an unbalanced translocation karyotype, two were karyotypically normal and four exhibited a balanced translocation identical with that of the parents. A therapeutic abortion was performed in the case of the unbalanced translocation, the two trisomic fetuses, and a male fetus of the haemophilia A carrier mother. After the abortion the prenatal chromosome findings were confirmed by cell cultures from fetal tissues. No immediate complications due to the amniocentesis were recorded, but two term fetuses died antenatally, one child was delivered prematurely, and one pregnancy terminated spontaneously foru weeks after the amniocentesis. Any casual relationship to the puncture was unlikely in these cases. All other pregnancies had a normal course and the outcome was in agreement with the prenatal studies. Although indications for prenatal karyotype analyses are evident in pregnancies at risk due to parental balanced translocation karyotype and advanced maternal age, the need for large-scale screening programmes is questionable, because the decision should be in the hands of the parents.

Amniocentesis↗
PubMed2026

Maternal age as a driver of genome instability: mechanisms linking aneuploidy, mutagenesis and mitochondrial dysfunction.

Advanced maternal age is a well-established risk factor for adverse reproductive outcomes due to increased rates of aneuploidy. However, emerging evidence indicates that the genetic consequences of maternal aging extend well beyond chromosome mis-segregation. Aging oocytes acquire a broad spectrum of genetic abnormalities, including maternally derived nuclear de novo mutations (DNMs) and mitochondrial DNA mutations, together with epigenetic dysregulation of DNA methylation and post-translational modification levels. These changes reflect the unique biology of the female germline in which oocytes remain arrested in meiotic prophase I for decades. Age-related deterioration of key processes, such as erosion of cohesion complexes, altered meiotic recombination, and weakened spindle assembly checkpoint surveillance collectively destabilize meiotic chromosome architecture, directly driving chromosome mis-segregation. At the same time, accumulation of endogenous DNA damage and declining DNA damage and repair processes increase the chances of transmitting lesions that can be converted into sequence-level mutations during the earliest embryonic divisions, when genome maintenance relies exclusively on maternal factors. High-resolution sequencing studies further demonstrate that maternal aging is associated with increased DNMs burden in both nuclear and mitochondrial DNA. Together, these findings support a model in which maternal aging is a driver of genome-wide instability that links aneuploidy and mutagenesis through shared defects in meiotic surveillance, declining DNA repair efficiency, and mitochondrial function. This framework positions delayed childbearing as a multifaceted genetic risk factor that extend beyond aneuploidy to include mutations and other genomic alterations that can impact intergenerational genetic risk.

Aneuploidy↗
PubMed2026

Prenatal SNP-array chromosomal microarray analysis in 3,549 pregnancies: indication-specific yields and clinical implications.

BACKGROUND: SNP-based chromosomal microarray analysis (CMA) is widely used in invasive prenatal diagnosis, yet real-world performance across contemporary referral pathways, especially in the NIPT era, remains incompletely characterized. METHODS: We retrospectively analyzed 3,549 prenatal invasive samples tested by SNP array, and evaluated diagnostic yield overall and by referral indication and ultrasound phenotype. RESULTS: In total, we identified 398 pathogenic or likely pathogenic (P/LP) variants across 386 fetuses, resulting in an overall diagnostic yield of 10.9% (386/3,549). These findings comprised 223 aneuploidies and 175 pathogenic CNVs. In contrast, variants of uncertain significance (VOUS) were detected in 12.0% (426/3,549) of cases. Diagnostic yields were heavily stratified by indication: yields peaked in NIPT high-risk referrals (38.9%) and were intermediate in ultrasound-based cases (~ 11%), but dropped significantly in the advanced maternal age (AMA; 4.2%) and serum screening (~ 5-6%) groups. Conversely, VOUS rates remained remarkably stable across all referral categories. Sub-analysis of ultrasound abnormalities revealed that multisystem anomalies conferred the highest risk (27.3%), driven predominantly by aneuploidies; among soft markers, increased nuchal translucency (NT) emerged as the strongest predictor of chromosomal pathology. CONCLUSIONS: In our cohort, SNP-array identified clinically actionable findings in 10.9% of cases. NIPT enriched diagnostic yields, particularly for aneuploidies, and NT thickness was strongly associated with pathogenic findings. These results support an indication-based approach to genomic testing, with NIPT as a triage tool for aneuploidy and CMA for high-risk populations, while improving VOUS counseling.

Humans↗
PubMed2026

IVF patient subgroups benefit from preimplantation genetic testing for aneuploidy: a prospective multicentre cohort study.

RESEARCH QUESTION: Can preimplantation genetic testing for aneuploidy (PGT-A) improve the ongoing pregnancy rate per transfer and reduce miscarriage rate in patients with advanced maternal age (AMA), recurrent implantation failure (RIF), recurrent pregnancy loss (RPL), or both, without affecting cumulative pregnancy rate? DESIGN: Prospective cohort study of 260 patients undergoing PGT-A aged 36 years or over (AMA group), with a history of three or more blastocyst transfers without birth (RIF group), two or more early pregnancy losses (RPL group), or all. Trophectoderm biopsy was conducted day 5 or 6, and comprehensive chromosome screening was used for PGT-A before single frozen embryo transfer (PGT-A-FET). A total of 3060 patients undergoing single conventional frozen embryo transfer (FET) served as a historical reference group. RESULTS: Patients had increased odds of positive serum beta-HCG after PGT-A-FET compared with FET in the AMA (OR 1.53, 95% CI 1.06 to 2.21) and RIF (OR 2.11, 95% CI 1.41 to 3.14) groups. The PGT-A-FET group significantly improved the odds of ongoing pregnancy in the AMA (OR 2.20, 95% CI 1.52 to 3.18), RIF (OR 3.96, 95% CI 2.60 to 6.04) and RPL (OR 2.81, 95% CI 1.52 to 5.21) groups. The odds of pregnancy loss were significantly reduced with PGT-A-FET in the AMA (OR 0.36, 95% CI 0.21 to 0.64), RIF (OR 0.10, 95% CI 0.04 to 0.26) and RPL (OR 0.14, 95% CI 0.04 to 0.53) groups. Cumulative pregnancy rate did not differ between PGT-A and conventional cycles (RR 0.94, 95% CI 0.80 to 1.10). CONCLUSIONS: PGT-A improved the odds of ongoing pregnancy and reduced the odds of pregnancy loss in all groups. The cumulative pregnancy rate did not differ between PGT-A and conventional cycles. Findings should be interpreted in the context of the observational design.

Adult↗
PubMed1979

[Prenatal diagnosis of trisomy-18-fetus of two women with chromosomal aberrations (author's transl)].

In two pregnant women a prenatal diagnosis was performed because of their advanced age. In both cases trisomy 18 was found. The mothers had chromosomal variations, not known until then. In one woman a structural aberrant chromosome No. 9 was found, the other woman had a gonosomal mosaic. In connection with the advanced maternal age these chromosomal findings possibly induced the trisomies in the children.

Adult↗
PubMed1979

Antenatal diagnosis of a de novo reciprocal translocation 46,XX,t(3;7)(q21;q11).

A de novo reciprocal translocation 46,XX,t(3;7)(q21;q11), detected at amniocentesis performed because of advanced maternal age, is presented. Both parents showed a normal karyotype. The girl was delivered and has shown no phenotypic abnormality in the first year after birth. Problems encountered with the prediction of the fetal outcome in balanced structural rearrangements are discussed.

Amniocentesis↗
PubMed1979

Familial transmission of a translocation Y/14.

A translocation of heterochromatic material, brightly fluorescent after actinomycin D-DAPI staining, to the short arm of chromosome 14 was prenatally detected during cytogenetic examination of cells obtained by amniocentesis on the indication of advanced maternal age. Besides this abnormal chromosome, 43 autosomes and two X chromosomes were present. Silver staining made clear that an active nucleolus-organizing region was included in the translocation product. Both the intense fluorescence and the size of the translocated extra heterochromatic block were indicative of a Yq origin. Upon cytogenetic investigation of the parents, the mother appeared to carry the same t(Y;14) chromosome. Therefore, we expected a normal girl to be born. This was confirmed after birth.

Adult↗
PubMedDate not supplied

Prenatal detection of anencephaly.

Fetal anomalies were suspected clinically in 3 patients, during the second trimester of pregnancy, due to advanced maternal age, hydramnios and abnormal vaginal bleeding respectively. Sonography revealed anencephaly in all of them, confirmed by roentgenograms and also by high amniotic fluid leveal alpha-fetoprotein in 1 of them. The antenatal diagnosis was confirmed in the 3 abortuses. Early screening of all pregnancies at risk for neural tube malformations is strongly recommended.

Adult↗
PubMed1979

Prenatal genetic diagnosis in 3000 amniocenteses.

We analyzed 3000 consecutive amniocenteses for prenatal diagnosis to assess the frequency of abnormalities, safety of the procedure, technical and interpretive difficulties and overall diagnostic accuracy. Chromosomal abnormalities were detected in 2.4 per cent of the 2404 pregnancies tested because of advanced maternal age (greater than or equal to 35 years), in 1.2 per cent of 240 monitored because of prior trisomy 21 and in 9.1 per cent of 55 examined for other cytogenetic indications. Mosaicism was detected in 0.4 per cent, and unexpected translocations in 0.4 per cent. Amniotic fluid was obtained on the first attempt in 99.3 per cent of the last 1000 cases, and cultures established from 99.7 per cent of patients attending our clinic. The fluid was discolored in 1.2 per cent of patients, a quarter of whom had missed abortions. The rate of spontaneous abortion after amniocentesis was 1.5 per cent. There were 14 diagnostic errors, six serious enough to affect the outcome of pregnancy. The karyotyping error rate was 0.07 per cent. We conclude that prenatal diagnosis is safe, highly reliable and extremely accurate.

Abortion, Spontaneous↗
PubMed2026

Maternal genetic variants associated with aneuploid conception: a narrative review.

BACKGROUND: Human aneuploid conception, a leading cause of infertility, pregnancy loss, and congenital disorders (e.g. Down's syndrome), arises from errors in chromosome segregation during oocyte meiosis or embryonic mitosis. While advanced maternal age is a well-established risk factor, significant inter-individual variation exists among younger women, suggesting a substantial role for maternal genetic determinants. OBJECTIVE AND RATIONALE: This review summarizes the identified maternal genetic variants associated with aneuploid conceptions and highlights directions for future research. SEARCH METHODS: We systematically searched PubMed, Embase, and the Cochrane Library (up to 12 January 2026), using key terms related to maternal genetics, genetic variants, aneuploidy, and pregnancy. Inclusion criteria were human studies, genetic confirmation of aneuploidy (in oocytes/embryos/products of conception/fetal cells), maternal variants (rare single-nucleotide variations, single-nucleotide polymorphisms, and small indels [≤50 bp]), and English-language publications. Exclusion criteria were non-human studies, structural/non-aneuploid numerical abnormalities, paternal factors, and conference abstracts. Extracted data items included study identifiers, population characteristics, variant details, detection methods, clinical phenotypes, type and origin of aneuploidy, pathogenicity or effect assessment, and gene inclusion in currently commercially available infertility next-generation sequencing (NGS) panels. Rare variants were classified per American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, whereas common variants were evaluated based on effect estimates and functional validation. Study quality was appraised using a modified Newcastle-Ottawa Scale. Supplementary searches explored associations between the identified genes and a broader range of reproductive phenotypes. OUTCOMES: From 28 studies covering the broad clinical spectrum of aneuploid pregnancies (including embryo arrest, implantation failure, pregnancy loss, hydatidiform mole, and fetal aneuploidy), we identified maternal variants associated with aneuploid conceptions. These were functionally categorized into meiotic recombination, spindle dynamics, checkpoint enforcement, and the maternal-to-zygotic transition. Among them, variants in several genes are supported by higher-quality evidence, including likely pathogenic rare variants in KIF18A, ELL3, and CEP120, as well as common variants in PLK4 and CCDC66. Although some identified genes (HFM1, MCM9, MEI1, BUB1B, NLRP2, NLRP7, and TLE6) are included in commercial infertility NGS panels, their direct association with aneuploidy requires further validation. WIDER IMPLICATIONS: This review proposes that 'aneuploidy predisposition' constitutes a critical, mechanism-driven dimension for the genetic diagnosis of infertility, complementing phenotype-based frameworks. This approach would best serve women with unexplained infertility and a normal karyotype who have either a history of recurrent aneuploidy or heterogeneous reproductive phenotypes across different cycles. Adopting this perspective refines clinical genetic testing paradigms and underscores the need to prioritize artificial intelligence-enhanced clinico-genomic association studies and develop polygenic risk models integrated with clinical factors. PROSPERO REGISTRATION NUMBER: CRD42025636217.

Humans↗
PubMed2026

Meiotic Origins of Non-Mosaic Klinefelter Syndrome (47, XXY): Mechanisms, Dimorphism, and Emerging Genetic Susceptibility.

BACKGROUND: Non-mosaic Klinefelter syndrome (47,XXY) arises from sex-specific meiotic mechanisms leading to nondisjunction during gametogenesis. In maternal cases, errors occur predominantly during meiosis I, frequently involving X chromosomes that lack crossovers or exhibit crossovers outside optimal chromosomal locations; this nondisjunction is further exacerbated by advancing maternal age and the subsequent deterioration of cohesins. Conversely, paternal 47,XXY stems primarily from the failure of obligate recombination within the pseudoautosomal region, which is critical for accurate XY segregation. OBJECTIVE: Drawing on the latest literature, this review transitions from a descriptive account of non-mosaic Klinefelter syndrome (nKS) toward a comprehensive analysis of mechanistic and genomic evidence, establishing a unified framework of sex-specific meiotic vulnerability. METHODS: We synthesized recent findings from forward genetic approaches in mouse models with data from human observational and reverse-genetic studies, delineating an updated view of the established and putative mechanisms that modulate sex chromosome segregation. RESULTS: We frame XX and XY nondisjunction as a genetically modulated process rather than a purely stochastic event. The integrated evidence supports a unified framework in which maternal and paternal mechanisms converge primarily on meiotic recombination failure but differ in timing, chromosomal context, and genetic modulation. CONCLUSIONS: From a clinical standpoint, identifying the molecular drivers of sex chromosome aneuploidy will enhance genetic counseling and risk stratification. Such insights are poised to facilitate informed reproductive decision-making and timely therapeutic support, ultimately reducing the burden of nKS comorbidities and improving patients' quality of life.

aneuploidy↗
PubMed1978

Hazards of amniocentesis: an unidentifiable fragment.

A 38-year-old woman had amniocentesis performed for advanced maternal age. The karyotype of the cultured amniotic fluid cells showed a minute fragment in all cells analyzed, 47,XY+Fg. The fragment could not be identified. For medical reasons the pregnancy had to be terminated at 34 weeks. Both skin and blood cultures from the aborted fetus showed a 47,XY,21+ karyotype.

Abortion, Induced↗