Introduction To date, only case reports regarding prenatal diagnosis of Silver-Russell syndrome (SRS) have been documented in the literature. In this study, we aim to elucidate the prenatal characteristics associated with SRS along with their molecular aspects. Methods This was a retrospective study of 23 cases with SRS. All cases received either prenatal or postnatal diagnoses of SRS with molecular confirmation harboring disease-causing defects in the mechanisms known to be associated with SRS. The medical records of patients were meticulously collected and reviewed. Results Of the 12 prenatally diagnosed cases, seven were identified due to intrauterine growth restriction (IUGR), two were detected following positive non-invasive prenatal testing results indicating trisomy 7, and three diagnoses were prompted by advanced maternal age. Of the 11 postnatally diagnosed cases, all exhibited IUGR in utero. Among all 18 cases presenting with IUGR, four were classified as early-onset IUGR, while the remaining 14 were diagnosed in the third trimester. Maternal uniparental disomy 7 accounted for the molecular defect in SRS in fifteen instances, followed by loss of imprinting center 1 methylation at 11p15 in five instances and maternal duplication of chromosome region 11p15.5 in another three instances. Conclusion Our findings highlight the significance of IUGR as a prenatal marker for SRS. Targeted molecular testing for SRS, including methylation-specific assays at key imprinted loci, should be integrated into the standard genetic evaluation of fetuses with unexplained IUGR.

Patients with genome-wide paternal uniparental disomy (GWpUPD) usually exhibit clinical features of Beckwith-Wiedemann syndrome (BWS) and a 46,XX karyotype, with all chromosomes showing isodisomy. To date, male patients with GWpUPD and a complete 46,XY karyotype, specifically involving heterodisomy, have not been described. We report a male infant exhibiting classical BWS clinical features. DNA methylation analyses showed paternal-specific methylation across multiple imprinted loci, suggesting GWpUPD. Genetic analysis of autosomes and sex chromosomes indicated two distinct paternal genomes in peripheral blood leukocytes, whereas a normal biparental genome was detected in other tissues under chimeric conditions. These findings indicated that the patient had genome-wide paternal uniparental heterodisomy (GWpUPhD). The SNP array revealed the presence of one copy of the X chromosome and one copy of the Y chromosome, the patient is a chimera composed of 46,XY biparental cells (with maternal X) and 46,XY GWpUPhD cells (with paternal X). This is the first report of a male patient with a GWpUPhD chimera. We propose a potential mechanism of GWpUPhD formation. Our findings expand the molecular spectrum of GWpUPD and provide valuable insights into its pathogenesis in chimeric conditions. Furthermore, the potential for clinical manifestations unique to 46,XY heterodisomy warrants careful long-term follow-up.

To describe the clinical characteristics of patients with Wolfram syndrome (WFS) and diabetes mellitus (DM) in Aotearoa, New Zealand. Review of response to therapy in those treated with glucagon-like peptide-1 receptor agonists (GLP1RA). This retrospective cohort study describes 7 patients with WFS1 genetic variants (1 patient with WFS-like syndrome), and DM from 5 New Zealand families (age range 5-33 years, 4 females, 3 males). All are receiving insulin. In 5 patients receiving GLP1RA therapy, we described their pre- and post-treatment biometric parameters, glycaemic control and visual acuity. Genetic testing identified compound heterozygous variants in the WFS1 gene (inherited from each parent) in five patients. Another two were heterozygous carriers of a single WFS1 missense variant, one of which was associated with uniparental disomy. Among patients receiving GLP1RA therapy, reductions were seen in HbA1c (mean 11.6 mmol/mol) and total daily insulin dose (mean 0.25 units/kg/day). We report genotypic and phenotypic variability in association with clinical features, including age of onset and severity. GLP1RA therapy was associated with improvements in diabetic control. Longer-term follow-up is required to monitor for sustained benefit and for progression or improvement in other WFS clinical features.

To report a rare prenatal case of paternal uniparental isodisomy of chromosome 3 (upd(3)pat) associated with isolated intrauterine growth restriction (IUGR). Expanded non‑invasive prenatal screening (NIPS) in a 19‑year‑old woman indicated a duplication on chromosome 3q. Amniocentesis was performed for karyotyping, chromosomal microarray analysis (CMA), and trio whole‑exome sequencing (WES). Copy number variation sequencing (CNV-seq) was performed for the validation of the placental tissue postpartum. Karyotype was normal (46,XY). CMA revealed a whole-chromosome region of homozygosity (ROH) on chromosome 3, and WES confirmed upd(3)pat with no recessive pathogenic variants. Third‑trimester ultrasound showed IUGR. A male infant weighing 2,450g was delivered at 38 weeks with normal birth examination. CNV-seq confirmed trisomy 3 on the fetal side of the placenta. Follow-up assessment at 2.5 years of age showed unremarkable neurodevelopmental outcomes. NIPS is a screening rather than a diagnostic test and all positive findings must be confirmed by invasive diagnostic procedures. Trisomy rescue can lead to coexistence of UPD3 with confined placental mosaicism (CPM). A multimodal approach incorporating karyotyping, CMA, trio‑WES, and CNV‑seq is essential for resolving discordant findings. This study expands the limited prenatal literature on upd(3)pat and highlights the critical importance of comprehensive genetic testing for accurate diagnosis and genetic counseling.

Uniparental disomy (UPD) is a rare chromosomal anomaly causing significant clinical implications in many affected individuals. In the case of UPD, a pair of homologous chromosomes or segments of it is inherited from only one parent. This can disrupt genomic imprinting, create long stretches of homozygosity, leading to diverse genetic and epigenetic syndromes. This scoping review has aimed to summarize postnatally reported UPD cases, tabulate chromosomespecific clinical characteristics, molecular diagnostic methodologies being utilized, and to formulate a standardised diagnostic workflow. A systematic literature search was conducted in PubMed, Scopus, and Web of Science up to 28 March 2025. Postnatally reported UPD cases were included. Extracted data comprised involved chromosomes, parental origin of disomy, clinical presentation of the affected individuals, and diagnostic approaches utilized. A total of 1507 UPD cases from 632 studies were analysed. UPDs were reported across all chromosomes, with the highest prevalence in chromosomes 11 (24.30%), 15 (18.64%), 7 (13.04%), and 14 (12.11%). The least affected were chromosomes 3, 9, 10, 12, 13, 17, 18, 19, 21, and X (<1% each). Mosaic UPD was identified in 15% of cases. Among the published cases, common clinical features included developmental delay, growth restriction, intellectual disability, and craniofacial dysmorphism. Most frequently employed diagnostic techniques included microsatellite/STR marker analysis, SNP microarray, methylation-specific MLPA, and whole-exome sequencing. Among all the chromosomes involved in UPD, the highest clinical relevance is observed in chromosomes 7, 11, 14, and 15. Among the techniques utilized for the detection and confirmation of UPDs, microsatellite/STR analysis is considered the gold standard. For higher efficiency and accuracy, better clinical interpretations, and proper genetic counselling opportunities, an integrated diagnostic workflow strategically targeting both genetic and epigenetic aspects is required. In this review, the clinical impact of different types of UPDs involving various chromosomes is highlighted. An integrated (epi/genetic) approach as a diagnostic framework is proposed.

Chromosome abnormalities are a known cause of miscarriage. A detailed chromosomal study in miscarriages is delineated using high-throughput technologies. 564 miscarriages were collected, and the chromosomal abnormalities, including triploidy, trisomy, monosomy, uniparental disomy, and chromosomal deletions/duplications in miscarriages, were detected by high-throughput single-nucleotide polymorphism (SNP) array. There were 336 (59.6%) miscarriages with chromosomal abnormalities, including 325 (57.6%) miscarriages with pathogenic variants and 11 (2%) miscarriages with variations of unknown significance (VOUS). The remaining 228 (40.4%) miscarriages had no clinically relevant chromosomal variants. Among the 325 miscarriages with pathogenic variants, 23 miscarriages had triploidy and two miscarriages showed genome-wide uniparental disomy. Trisomy was found in 225 miscarriages and involved nearly every chromosome. Monosomy X was found in 39 miscarriages. Also, 32 miscarriages were with partial chromosomal deletions/duplications, particularly in 8p23 and Xp22 regions. Our results confirmed that trisomy and monosomy X are potentially the most common causes of miscarriage. We also showed that chromosomal pathogenic deletions/duplications are involved with miscarriage. However, still nearly 40% of miscarriages had no chromosomal variants detected by SNP array. This may be attributed to a single gene mutation that requires high-throughput sequencing.

Congenital adrenal hyperplasia (CAH) due to 21‐hydroxylase deficiency (21‐OHD CAH) is an autosomal recessive genetic condition that results from pathogenic variants in the CYP21A2 gene. Noncarrier parents are found in a small percentage of cases, typically due to de novo variants. However, uniparental disomy (UPD) should also be considered. UPD is generally suspected when an individual with an autosomal recessive condition is found to be homozygous for a rare pathogenic variant and consanguinity has been ruled out. However, UPD in CYP21A2 may be hard to recognize because homozygous genotypes are not uncommon. We present the case of a 19‐month‐old male born preterm who presented to pediatric endocrinology after a positive newborn screen for CAH. He was small for gestational age, with a history of adrenal crisis and elevated 17‐hydroxyprogesterone (17‐OHP). Genetic testing revealed homozygosity for two common pathogenic CYP21A2 variants: c.293‐13C >G and c.1360C >T (p.Pro454Ser), both variants were found in the heterozygous state in the mother while the father’s CYP21A2 molecular testing was negative. UPD testing was pursued and the results were consistent with the patient having maternal isodisomy of chromosome 6. In cases of patients with CAH due to homozygous CYP21A2 variants, suspicion for UPD may be increased if the child also presents with intrauterine growth restriction (IUGR), or transient neonatal diabetes (TNDM) mellitus, associated with maternal and paternal UPD of chromosome 6, respectively.

Mutation or uniparental disomy? Evaluating abnormal inheritance patterns using Object-Oriented Bayesian Networks.

Observations and investigation of STR genotype inconsistencies due to mutations, silent alleles, and uniparental disomy in South African populations.

To investigate the incidence, positive predictive value (PPV) and pregnancy outcomes of rare autosomal trisomies (RATs) identified by non-invasive prenatal testing (NIPT). A retrospective analysis of pregnancies who underwent NIPT at our center between May 2020 and August 2024 and received high-risk RATs results. A copy number (CN)≥2.4 indicated high-risk for maternal duplications, while a CN≤1.6 correlated with maternal deletion. Targeted amplicon sequencing was utilized to screen for uniparental disomy (UPD)-related imprinting disorders. Prenatal diagnosis and pregnancy outcome follow-up were recommended for all high-risk pregnancies. Among 20,796 pregnancies screened, 0.26% (55/20,796) were identified as high-risk for RATs. Prenatal diagnosis was performed in 44 cases, with a PPV of 4.55%. Maternal copy number variations were confirmed in four cases, three of which were transmitted to the fetus. No UPD-related imprinting disorders were detected in the 23 cases. Two cases of mosaic trisomy showed similar levels of mosaicism on chromosomal microarray analysis (CMA) but had divergent clinical outcomes. Among 36 cases with no abnormalities detected by prenatal CMA, 38.89% had adverse outcomes. NIPT for RATs has a low PPV, but the risk of adverse outcomes is high. Mosaic RATs identified via amniocyte-based prenatal diagnosis do not always correlate with an obvious postnatal phenotype. Integrating prenatal diagnosis with ultrasound monitoring is essential for fetal prognosis.

Chromosomal abnormalities are a leading cause of early pregnancy loss (EPL). While copy number variation sequencing (CNV-seq) is gradually applied in clinical practice, its sensitivity for detecting triploidy and uniparental disomy (UPD) remains limited. This study aimed to evaluate whether integrating CNV-seq with short tandem repeat (STR) genotyping could improve diagnostic performance in EPL. In this study, 572 EPL samples were examined using CNV-seq combined with STR genotyping to detect chromosomal abnormalities, including triploidy and UPD, and to explore STR-based approaches for identifying the origin of abnormal chromosomes. Selected results were validated using karyotyping, CMA, MLPA, or FISH when necessary. Chromosomal abnormalities were identified in 313 cases (54.7%), including autosomal aneuploidies (52.4%), CNVs (13.4%), sex chromosome aneuploidies (11.5%), multiple trisomies (3.5%), and mosaicism (3.5%). STR genotyping identified 38 additional cases (35 triploidy, 3 UPD) missed by CNV-seq, elevating the overall diagnostic yield by 6.6% (p < 0.05). Parental origin analysis revealed distinct distribution patterns: 69,XXY triploidies were predominantly of paternal origin (80.8%), whereas 69,XXX cases were mostly maternal (88.9%); all detected UPD cases were paternally derived. Among 134 common autosomal aneuploidies, maternal meiotic errors accounted for 91.8% of occurrences. The combination of CNV-seq and STR genotyping significantly improves the detection efficiency of triploidy, mosaicism, and other complex chromosomal anomalies, compensating for crucial limitations of conventional CNV-seq.Further STR-based parental tracing facilitates the identification of chromosomal aberration origins and reveals error formation patterns, thereby providing robust evidence for clinical etiological interpretation of early pregnancy loss.

Silver-Russell syndrome (SRS) is a rare congenital imprinting disorder associated with the loss of methylation in H19/IGF2:IG-DMR at chromosome 11p15.5 (11p15 LOM) or maternal uniparental disomy of chromosome 7 (upd(7)mat). Longitudinal analysis of somatic development was performed in 99 Polish patients with Silver-Russell syndrome: 82 (82.8%) with 11p15 LOM, 17 (17.2%) with upd(7)mat, without growth hormone therapy. All patients were assessed by a clinical geneticist and molecular tests were taken. Birth parameters were analyzed. Weight, height, BMI, and chest-to-head proportions were collected cross-sectionally and in different stages of development (every year, until the age of 16-18y). ROC analysis showed good diagnostic performance of head-chest proportionality indices in distinguishing SRS patients from SGA patients at birth. The difference between head and chest circumference demonstrated an AUC of 0.840 (95% CI 0.768-0.912), increasing to 0.850 (95% CI 0.771-0.929) after exclusion of preterm infants, while the chest-to-head ratio showed an AUC of 0.812 (95% CI 0.732-0.892) and 0.827 (95% CI 0.741-0.912), respectively. These simple indices, derived from routine neonatal measurements, may support early identification of SRS among SGA infants. Moreover chest-to-head circumference proportion in SRS patients does not change until the age of 9 years in boys and 8 years in girls. Long-term studies showed that body height, weight, weight-for-height, and BMI were higher in patients with 11p15LOM up to the age of 10-12; however, this trend reverses later in favor of the upd(7)mat group. The introduction of head and chest circumference measurement into routine clinical examination may be useful, especially when the diagnosis of SRS is based solely on clinical symptoms. Long-term studies have shown a tendency for changes in body weight, height, and BMI depending on age and molecular abnormalities.

STUDY QUESTIONWhat is the incidence of triploidy and genome-wide uniparental disomy (gwUPD) in human embryos currently undetected by conventional preimplantation genetic testing (PGT)?SUMMARY ANSWERTriploidy and gwUPD were detected in 0.8% (8/1049) and 1.4% (15/1049) of blastocysts, respectively.WHAT IS KNOWN ALREADYConcurrent PGT enhances embryo selection by simultaneously detecting monogenic disorders (PGT-M) or structural rearrangements (PGT-SR) and aneuploidy (PGT-A). However, triploidy and gwUPD, two genome-wide abnormalities causative of severe pregnancy outcomes, are not routinely detected by conventional PGT platforms and thus remain under-recognized at the preimplantation stage.STUDY DESIGN, SIZE, DURATIONThis study consisted of three phases: Phase I validated the detection capability of PGT-Plus on cell lines with previously ascertained genetic abnormalities; Phase II performed retrospective clinical validation on leftover trophectoderm biopsy whole-genome amplification (WGA) samples, including 65 for PGT-M, 67 for PGT-SR, and 130 for PGT-A received during January 2019 and July 2023; and Phase III was prospective implementation of PGT-Plus under a diagnostic setting on 529 blastocysts received from August 2023 to June 2024. Additionally, a cohort consisting of 258 embryo transfers, previously ascertained as euploid by conventional PGT-A methods but associated with unfavorable outcomes, was retested by PGT-Plus, which identified previously undetected cases of gwUPD or triploidy.PARTICIPANTS/MATERIALS, SETTING, METHODSIn Phase I, cell lines with ascertained genetic abnormalities were tested using at least one of the following methods, including G-banded Karyotyping, quantitative fluorescence PCR (QF-PCR), chromosomal microarray analysis (CMA), and mate-pair sequencing. The previous results were compared with those from PGT-Plus. In Phase II, results from conventional PGT platforms were compared in parallel with PGT-Plus to evaluate its accuracy. Cell lines or real trophoblast biopsy samples from blastocysts were amplified by the multiple displacement amplification (MDA) method. PGT-Plus data analysis was performed in various dimensions. For PGT-A analysis, except for canonical read-count analysis to assess the genome dosage, single nucleotide polymorphism (SNP) analysis was also performed to identify triploidy and gwUPD. Furthermore, for families requesting PGT-M and PGT-SR, linkage analysis was carried out for haplotype construction in addition to read-count analysis and SNP analysis. In addition to prospective cohort of Phase III, a unique cohort with adverse reproductive outcomes after transfer of a ‘euploid’ embryo, as determined by conventional PGT-A platforms, was retested to identify any triploidy and UPD among these copy-number neutral embryos. The unfavorable outcomes included no pregnancy, biochemical pregnancy, miscarriage, and termination of pregnancy due to fetal anomaly.MAIN RESULTS AND THE ROLE OF CHANCEPGT-Plus detected all abnormalities ascertained by prior platforms in Phases I and II. In total, triploidy and gwUPD were detected in 0.8% (8/1049) and 1.4% (15/1049) of blastocysts, respectively. Notably, 3.5% (9/258) of the unfavorable transfers of embryos previously classified as ‘euploid’ would have been prevented if triploidy and gwUPD were detected. In addition, 45.7% (12/35) of embryos previously classified as balanced by PGT-SR were translocation carriers.LIMITATIONS, REASONS FOR CAUTIONPGT-Plus, similar to other relative phasing methods, requires an additional family member for haplotype determination, although an embryo with a known genotype via prior independent testing is also acceptable. In addition, short-read next-generation sequencing (NGS) impedes the capacity of PGT-Plus to directly detect pathogenic SNVs located in highly repetitive regions of the genome, e.g. the HBA1 gene causative of thalassemia, which still require conventional methods, including short tandem repeats and PCR, to safeguard clinical diagnosis or can be addressed by long-read sequencing.WIDER IMPLICATIONS OF THE FINDINGSThis newly established PGT-Plus approach additionally detected gwUPD and triploidy in preimplantation embryos. It explained another 3.5% of ‘euploid’ embryo transfer failures. Meanwhile, embryo selection was enhanced by integrating PGT-M, PGT-SR, or PGT-A with an analysis of parental origin and stage of non-disjunction within a single PGT-Plus workflow.STUDY FUNDING/COMPETING INTEREST(S)This work was funded by the Research Grant Council Collaborative Research Fund (grant no. C4062-21GF to K.W.C.), the National Natural Science Foundation of China (grant no. 82502033 to Y.L.), and the Research Grant Council General Research Fund (grant no. 14100822 to J.P.W.C.). All authors declare that they have no conflicts of interest.TRIAL REGISTRATION NUMBERN/A.

We evaluated the diagnostic yield of karyotype (KT) and chromosomal microarray (CMA) with isolated severe FGR diagnosed before 32weeks' gestation. Exome and genome sequencing (ES/GS) level data were available in a subset of this population. We performed a retrospective review of singleton pregnancies (delivered 2022-2025) with estimated fetal weight or abdominal circumference <3rd percentile before 32weeks' gestation, no sonographic structural anomalies, and diagnostic testing (KT, CMA, ES, or GS) via amniocentesis or cord blood. Cases with abnormal cell-free DNA were excluded. Forty cases were included (mean diagnosis 26.8weeks). Testing was performed via amniocentesis in 42% and cord blood in 58%. All KT (27/40) were normal. CMA (39/40) identified one pathogenic CNV (2.5%) and three (7.5%) variants of uncertain significance (VUS). Four (10%) showed ≥ 1 region of absence of heterozygosity (AOH)>10Mb; one revealed maternal uniparental disomy of chromosome 6. Sequencing (N=10) detected one VUS in COL1A1. Acute viral infection was not observed in any of the cases. CMA was diagnostic in 2/39 (5.1%) cases, a pathogenic CNV implicating the SHOX gene, and maternal UPD 6, which were consistent with FGR. There was a remarkable rate (10%) of AOH. Further investigation, including placental studies and genome sequencing, may elucidate whether AOH is a contributing factor for FGR.

Germline gain-of-function variants in sterile alpha motif domain-containing 9-like (SAMD9L), located on chromosome 7q, cause a multisystem disorder characterized by bone marrow failure, immunodeficiency and variable neurological involvement. Disease evolution is frequently shaped by somatic genetic rescue (SGR), most commonly through monosomy 7, somatic loss-of-function (LOF) variants in cis or uniparental disomy of 7q (UPD7q). We report a 6-month-old girl presenting with pancytopenia and severe infections, in whom we identified a novel heterozygous SAMD9L variant. Trio-based whole-genome sequencing demonstrated maternal transmission and revealed distinct SGR mechanisms in both the proband and her asymptomatic mother, including UPD7q and an additional somatic LOF variant. Longitudinal molecular follow-up showed dynamic clonal evolution associated with haematological improvement. To assess the broader relevance of SAMD9/SAMD9L variants, we also performed a gene-centred analysis of the 2025 French Genomic Medicine Initiative (PFMG2025), enabling the identification and classification of additional candidate variants. These findings support systematic screening for SGR, including mosaic UPD7q, even in cases with apparently normal variant allele frequency, and highlight the importance of integrating haematopoietic and non-haematopoietic tissues in diagnostic workflows for inherited bone marrow failure syndromes.

Imprinting disorders are caused by epigenetic alterations leading to abnormal gene expression from imprinted loci. Pseudohypoparathyroidism type 1B is characterized by methylation defects at the GNAS locus, affecting hormone responsiveness. Monozygotic twins discordant for imprinting disorders provide a unique opportunity to investigate the timing, maintenance, and tissue-specific distribution of epimutations and their relation to clinical expression. Most previous studies focus on infants, where fetal blood chimerism may influence epigenetic profiles, but data in adolescents remain scarce. We studied adolescent monozygotic twin sisters presenting clinical and biochemical discordance for pseudohypoparathyroidism type 1B. Both twins exhibited an identical, partial methylation defect at the GNAS locus in peripheral blood, consistent with a postzygotic epigenetic alteration occurring before embryonic splitting. Exclusion of known genetic causes, including uniparental disomy and structural variants, and absence of multilocus imprinting disturbances or maternal-effect gene mutations, were confirmed through comprehensive genomic and methylation analyses. The affected twin showed involvement of methylation abnormalities across all three germ layers derived tissues, whereas the unaffected twin presented very mild or absent defects in some tissues, possibly explaining the phenotypic divergence. The persistent concordance of partial methylation defects in blood despite phenotypic discordance suggests stable early epimutations maintained in hematopoietic progenitors, while tissue-specific mosaicism and differential methylation maintenance across organs critical to disease expression contribute to clinical differences. Advanced long-read sequencing demonstrated sensitivity for detecting partial and mosaic methylation patterns, rather than just complete alterations. This study underscores the complexity of epigenetic mosaicism in imprinting disorders, highlighting that early postzygotic partial epimutations may yield identical blood methylation profiles but divergent tissue distributions, leading to discordant clinical phenotypes in monozygotic twins. The adolescent age of our subjects challenges the fetal blood chimerism explanation for methylation concordance and emphasizes the importance of multi-tissue evaluation and sensitive molecular assays. These findings have important implications for diagnosis, monitoring, and genetic counseling in imprinting disorders, advocating for integrated approaches to assess epigenetic heterogeneity and phenotypic variability.

To evaluate the efficacy and clinical value of combining low-depth whole-genome copy number variation sequencing (CNV-seq) with short tandem repeat (STR) polymorphism analysis in the genetic diagnosis of spontaneous abortion. Products of conception and clinical data were retrospectively collected from 553 patients who underwent abortion surgery at Guiyang Maternal and Child Health Care Hospital between January 2023 and October 2024. All samples were tested by CNV-seq to detect copy number variations (CNVs) ≥ 100 kb and aneuploidies. STR analysis was performed in parallel to identify abnormalities undetectable by CNV-seq alone, such as triploidy and uniparental disomy (UPD). The correlation between the detection rate of chromosomal abnormalities and factors including maternal age, gestational week, conception method, and history of adverse pregnancy was analyzed. This study was approved by the Medial Ethics Committee of the Guiyang Maternal Child Health Care Hospital (Ethics No.: 2025-10). The initial detection rate of chromosomal abnormalities by CNV-seq alone was 52.98% (293/553). After integrating STR results, 23 cases of triploidy and 1 case of UPD were additionally identified, increasing the overall detection rate to 57.32% (317/553). Autosomal aneuploidy was the most common abnormality (48.26%, 153/317), followed by aneuploidy mosaicism (20.82%, 66/317), sex chromosome aneuploidy (10.41%, 33/317), and pathogenic CNVs (10.41%, 33/317). The most frequent numerical abnormalities were trisomy 16 (9.15%), 45,X (7.57%), and triploidy (7.26%). The chromosomal abnormality detection rate was significantly higher in women of advanced maternal age (≥ 35 years) (67.55%, 102/151) than in those < 35 years (53.73%, 215/402), and significantly higher in the early miscarriage group (< 12 weeks) (60.20%, 307/510) than in the late miscarriage group (20.93%, 9/43) (both P < 0.05). No significant differences in chromosomal abnormality rates were found between the assisted reproductive technology (ART) and natural conception groups, or between groups with ≤ 2 or > 2 previous adverse pregnancies (both P > 0.05). The combined application of CNV-seq and STR polymorphism analysis improves the detection rate of genetic causes in spontaneous abortion. Advanced maternal age and early miscarriage are key risk factors for embryonic chromosomal abnormalities, while ART conception and a limited history of previous abortions showed no significant impact in this study. This integrated strategy provides a reliable basis for the precise etiological diagnosis of abortion and subsequent genetic counseling.

SUMMARYThe human cortex acquires its advanced cognitive capacity through tightly regulated developmental programs, disruption of which underlies neurodevelopmental disorders such as Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). While SYS results from pathogenic variants in the imprinted gene MAGEL2, PWS arises from chromosomal deletions, imprinting defects or uniparental disomy encompassing the MAGEL2 locus. However, the contribution of MAGEL2 to disease pathogenesis and human corticogenesis is not fully understood. Here, we performed integrated transcriptomic, proteomic, and ubiquitinomic profiling of cortical neurons derived from CRISPR/Cas9-engineered isogenic human pluripotent stem cells (hiPSC) modeling SYS and PWS. Beyond PWS-specific signatures including dysregulated ribosomal processes, we identified MAGEL2-dependent defects shared across both disorders. These include reduced progenitor proliferation, accelerated neuronal maturation, impaired migration and adhesion, as well as abnormal synaptic development, collectively linking PWS and SYS at the level of cortical development. Notably, these phenotypes partially overlap with those observed in other neurodevelopmental disorders, suggesting that MAGEL2 governs core pathways broadly vulnerable in disease. Together, our findings establish MAGEL2 as a key regulator of human cortical development, provide a unifying mechanistic framework for SYS and PWS, accessible via a web-based platform.

Genome-wide noninvasive prenatal testing has introduced new challenges in clinical interpretation, for example, due to discrepancies between noninvasive prenatal testing and confirmatory invasive results caused by confined placental mosaicism. These discordant cases often involve rare autosomal trisomies, frequently attributed to placental mosaicism. Complex, multichromosomal false-positive genome-wide noninvasive prenatal testing results are usually not due to placental mosaicism but rather to maternal malignancy, for example. This study aimed to assess chromosome-specific associations with pregnancy complications and uniparental disomy in false-positive rare autosomal trisomies and the prevalence of maternal malignancies in complex, multichromosomal genome-wide noninvasive prenatal testing results. A systematic search of 5 databases-MEDLINE (via PubMed), Embase, Cochrane, Scopus, and Web of Science-was conducted on August 28, 2025. Cohort studies using massively parallel sequencing were included. The study population was pregnant women who had undergone genome-wide noninvasive prenatal testing and had a known pregnancy outcome. Data extraction followed a standardized protocol, risk of bias was assessed using the Quality in Prognostic Studies tool, and statistical analyses were performed in R (v4.1.2) using a random-effects model. Sixteen eligible studies encompassing 681,633 pregnancies were included. Rare autosomal trisomy-positive results occurred in only 0.2% of cases and 80% were false positives. Notably, ∼35% of these were associated with adverse pregnancy outcomes, predominantly involving chromosomes 2, 4, 11, 16, and 22. Uniparental disomy was most commonly associated with trisomies 15 and 16. In cases with complex genome-wide noninvasive prenatal testing findings, 40% were ultimately diagnosed with maternal malignancy, primarily breast cancer and lymphoma. Discordant genome-wide noninvasive prenatal testing results are associated with an increased risk of placenta-mediated complications. Among rare autosomal trisomies, trisomy 16 and, to a lesser extent, trisomy 4 consistently showed the highest risks. These results imply that chromosome-specific risk stratification could inform prenatal counseling and follow-up. Additionally, complex, multichromosomal genome-wide noninvasive prenatal testing results were occasionally associated with maternal malignancies. This emphasizes the importance of considering both maternal and fetal contributions when interpreting such results.

Aplastic anemia (AA) results from T-cell-mediated destruction of hematopoietic stem and progenitor cells (HSPCs), driving clonal hematopoiesis via loss of human leukocyte antigen (HLA) risk alleles (HLA loss-of-function mutations or uniparental disomy 6p, UPD6p), paroxysmal nocturnal hemoglobinuria and clonal hematopoiesis of indeterminate potential (CHIP) mutations. Here genomic profiling of 619 patients with AA revealed clonal hematopoiesis in 69% of cases, with ASXL1, BCOR and BCORL1 identified as the most frequent CHIP mutations in pediatric cases. Single-cell multi-omics analysis of 304,902 cells from 48 samples uncovered complex branching clonal architecture, with a median of three HLA loss events per patient, converging to inactivate HLA risk alleles. Single-cell whole-genome sequencing (WGS) resolved up to 15 HLA loss clones per patient and phylogenetic reconstruction indicated that these clones originated years before diagnosis. Long-read WGS precisely mapped UPD6p breakpoints and HLA methylation. HLA loss conferred a protective effect against CHIP, evidenced by their near-absent co-occurrence. Longitudinal single-cell analysis demonstrated that long-lived clones were enriched in the CD34+ HSPC compartment. These findings reveal parallel evolutionary pathways used by hematopoietic cells to evade immune attack.