Chromosomal Microarray Research Articles

Identification of a novel microdeletion at 9q21.13 in a family with epilepsy, intellectual disability, and speech disorders and literature review

BackgroundAt present, there are few reports on 9q21.13 microdeletion syndrome, which is characterized by intellectual disability, epilepsy, autistic behaviour, and recognizable facial features, etc. The aim of this study is to enrich the phenotypic features of 9q21.13 microdeletion syndrome and expand the possible segments of 9q21.13 microdeletion syndrome.MethodsFour individuals from a 3-generation Chinese family with epilepsy, intellectual disability, and speech disorders were recruited in this study. Whole exome sequencing (WES) and chromosome microarray analysis (CMA) techniques were used for genetic testing. The pathogenicity of CNVs was interpreted following the American College of Medical Genetics (ACMG) standards and guidelines.ResultsA 9q21.13 microdeletion with a fragment size of approximately 2.35 Mb was identified in the proband, the proband’s mother and grandmother and even the fetus. And this region encompasses 6 protein coding genes, namely, ALDH1A1, ANXA1, GDA, RORB, TMC1, and ZFAND5.ConclusionIn this article, we report a girl with epilepsy, intellectual disability, speech disorders, delayed motor development, and autism. We identified a novel 9q21.13 microdeletion with a fragment size of approximately 2.35 Mb in 4 individuals from a 3-generation Chinese family by WES and CMA techniques. Within the region, the RORB gene is a strong candidate gene for complex neurodevelopmental disorders. Herein, we speculate that RORB makes a significant contribution to the clinical phenotypes caused by 9q21.13 microdeletion.

A Prospective Evaluation of the Diagnostic Utility for Low-Coverage Genome Sequencing in Prenatal Samples: A Comparison With Chromosomal Microarray Analysis.

The present study aimed to evaluate the efficacy of LC-GS in detecting clinically relevant chromosomal abnormalities in comparison with conventional CMA within a prenatal context. We conducted a prospective study involving 200 amniotic fluid samples. All specimens were analyzed via LC-GS and traditional tests, including CMA and karyotyping. LC-GS was performed with 3X coverage to gauge its proficiency in identifying copy number variations (CNVs), aneuploidies, regions of homozygosity (ROH), and chromosome mosaicism. Data from both methods were compared to evaluate their sensitivity, specificity, and overall clinical utility. LC-GS at a depth of 3X identified a total of 77 positive samples, yielding a detection rate of 38.5% (77/200). This included 17 cases of aneuploidy, 36 instances of CNVs, 20 cases linked to ROH, and 8 cases of chromosomal mosaicism. LC-GS demonstrated high concordance with CMA in aneuploidy, CNVs, ROH, and chromosomal mosaicism, achieving a diagnostic yield of 21% (42/200), with additional benefits of reduced cost. Moreover, LC-GS outperformed CMA in terms of resolution for identifying submicroscopic CNVs. LC-GS presents a robust alternative to CMA for prenatal diagnosis, effectively identifying aneuploidies, CNVs, chromosomal mosaicism, and ROH. It delivers comparable sensitivity and specificity in the detection of a wide spectrum of genomic abnormalities.

Novel ANKRD17 variants implicate synaptic and mitochondrial disruptions in intellectual disability and autism spectrum disorder

ANKRD17 has recently been implicated in intellectual disability (ID) and autism spectrum disorder (ASD); however, the underlying molecular mechanisms remain unclear. Using trio whole-exome sequencing (Trio-WES) and chromosomal microarray analysis (CMA), we identified two unrelated cases with novel de novo heterozygous ANKRD17 variants. Case 1 describes a fetus with multiple congenital anomalies, where genetic analysis revealed a microdeletion at 4q13.3 truncating the ANKRD17 gene. Case 2 involves a 12-year-old male presenting with mild ID and progressive social impairments, associated with a NM_032217.5: c.1252 C > T (p.Arg418*) variation in ANKRD17. Our study highlighted in mouse models an association between Ankrd17 haploinsufficiency and deficits in social behavior, spatial learning and memory, as well as elevated anxiety. Furthermore, our studies suggest dysregulation of synaptic proteins and mitochondrial function, along with impaired neural circuits following Ankrd17 knockdown. These results expand the genetic and phenotypic spectrum of ANKRD17-related disorders, underscore the critical role of mitochondrial dysfunction in the pathophysiology of ANKRD17-related ID and ASD.

Predicting cisplatin response in cholangiocarcinoma patients using chromosome pattern and related gene expression

Cholangiocarcinoma (CCA) is a prevalent bile duct cancer with limited treatment options. Cisplatin-based chemotherapy is a common approach, but response rates vary. Recently, chromosome aberrations have emerged as predictors of chemotherapy response in various malignancies. This study aimed to identify chromosomal aberrations associated with cisplatin response in CCA. A histoculture drug response assay was conducted on 20 fresh CCA tissues to determine cisplatin sensitivity. In parallel, chromosome aberration analysis was performed using chromosome microarray. Using chromosome microarray analysis on 20 CCA samples, we found distinct chromosomal aberration patterns between cisplatin responders and non-responders. Gains in 18q and 20q, and losses in 1p and 8p were more common in non-responders. Conversely, the responders exhibited gains in 8q and losses in 16q. Our heatmap analysis of log-2 ratio demonstrated difference in various chromosomes including 2, 3p, 5q, 6q, 7, 9p, 11q, 14q, 15q, 18q, 20q, and 22q between the response and the non-response to cisplatin. Further analysis using machine learning with random forest model identified genes like NCOA3, TPK1, CEP57L1, DEPDC5, and PLXNA4 as potential predictors of cisplatin response. Validation in a separate cohort of 33 CCA samples confirmed the association of NCOA3 and DEPDC5 with cisplatin response. Our findings suggest that chromosomal aberrations and specific genes may predict cisplatin response in CCA, potentially guiding personalized treatment strategies.

Jurkat T-cell lines exhibit marked genomic instability affecting karyotype, mutational profile, gene expression, immunophenotype and function

The Jurkat cell line, derived from a case of T-cell lymphoblastic leukaemia, is widely employed as a model T-cell for biomedical research, including for the preclinical characterisation of cellular therapies such as chimeric antigen receptor T-cells. Here, we characterised genomic, transcriptomic, and functional features of Jurkat clone E6-1 cells from three different laboratories and compared these with Jurkat E6-1 cells from the American Type Culture Collection (ATCC). We identified marked karyotypic heterogeneity both between and within Jurkat E6-1 populations, confirmed through chromosomal microarray. Whole exome sequencing of each cell population revealed both shared and unique mutational profiles, and transcriptomic profiles varied markedly between Jurkat E6-1 cell populations. Finally, the Jurkat E6-1 cell populations exhibited substantial variations in immunophenotype and cytokine production, which were consistent with the genotypic and transcriptomic changes observed. In summary, we identify substantial genomic heterogeneity both between and within Jurkat E6-1 cell populations, highlighting the genomic instability of this line. These genomic changes were associated with differences in protein expression and cytokine production that may affect functional assays. Our findings highlight the importance of monitoring cell passage number, characterising cell lines, and replacing cell line stocks to assure the accuracy, reproducibility, and translatability of assays employing Jurkat E6-1 cells.

The genetic spectrum features of 2261 Chinese children with epilepsy and intellectual disability

BackgroundEpilepsy (EP) and intellectual disability (ID) are two highly correlated diseases that seriously impact neurodevelopment in children. Precision diagnosis of EP and ID remains challenging due to their clinical and genetic heterogeneity, necessitating a profound understanding of disease characteristics.MethodsWe provide a clinical and genetic landscape of 2261 Chinese patients performed chromosome microarray analysis (CMA) or next-generation sequencing to uncover causal copy number variants (CNVs) or single-nucleotide variants (SNVs). Patients were stratified into three groups: EP (374 cases), ID (863 cases), and EP + ID (1024 cases).ResultsWe reported a 24.3% diagnostic yield from 496 causal CNVs and SNVs, including 182 novel variants, in which updated 33 previously reported VUS. Significant intergroup differences emerged: EP patients were predominantly caused by autosomal dominant SNVs, showing the highest rates of incomplete penetrance and family history. ID patients were more likely caused by CNVs and autosomal recessive SNVs, with the highest genetic heterogeneity. EP + ID patients displayed the earliest onset ages and highest diagnostic yields. We prioritized genes by diagnostic efficiency and revealed that X-linked SNVs disproportionately affected females, particularly in the EP + ID group, under current diagnostic paradigms. This real-world dataset informs genetic counseling, testing strategies, precision therapies, and long-term management for EP/ID.ConclusionsThe clinical and genetic profiles from this study provided a reliable baseline reference for diagnosing EP and ID.

Prenatally and postnatally sequential genetic etiology detection in corpus callosum abnormalities

To evaluate the clinical utility of genetic testing via karyotyping, chromosomal microarray analysis (CMA), and exome sequencing in cases with corpus callosum abnormalities (CCA). Here, 65 prenatal and 12 postnatal cases diagnosed with CCA via ultrasound and magnetic resonance imaging examination were enrolled. All cases were divided into two groups: 21 (27.3%) isolated and 56 (72.7%) non-isolated CCA groups. Karyotyping and CMA were first performed in parallel, then followed by whole exome sequencing (WES) after negative karyotype and CMA results. Clinical outcomes were also followed up. Karyotype abnormalities were identified in 7 cases (9.1%, 7/77). Karyotype abnormality rates in the isolated and non-isolated CCA groups were 8.0% and 9.6%, respectively (p > 0.05). Pathogenic/likely pathogenic (P/LP) CNVs were identified in 11 cases (14.3%, 11/77), including 2(9.5%, 2/21) and 9(16.1%, 9/56) cases in the isolated and non-isolated CCA groups, respectively (p > 0.05). WES identified P/LP diagnostic genetic variants in 8 (47.1%, 8/17) cases, including 2 and 6 cases in the isolated and non-isolated CCA groups, respectively. Additionally, 3 cases with variants of unknown significance were identified. Of the 65 prenatal cases with CCA, 31 (47.7%) were terminated, 1 (1.5%) was a miscarriage, 33 (50.8%) yielded live born babies; of these, 4(12.1%, 4/33) yielded babies with neurodevelopment disorders (NDDs). Of the 12 postnatal cases with CCA, all presented NDDs. Genetic causes of CCA are highly variable. Prenatal brain magnetic resonance imaging and systemic ultrasound examination should be performed to examine other anomalies when CCAs are detected via ultrasound. WES is also recommended following negative karyotype and CMA results.

Role of Genetic and Epigenetic Factors and Mechanisms Involved in the Occurrence of Congenital Heart Diseases (CHD)

Introduction: Congenital heart diseases (CHD) are complex, multifactorial cardiac disorders that result from a combination of genetic, environmental, and epigenetic factors, with genetic factors being particularly prominent. This remarkable disease affects approximately 1% of newborns and can occur sporadically and familially. Sporadic cases are often associated with novel mutations or newly emerging chromosomal abnormalities, while familial cases show different inheritance patterns. Advanced research in molecular genetics, especially techniques such as whole-exome sequencing and chromosomal microarray analysis, which focus on protein-coding regions of the human genome, has identified hundreds of genes associated with the development of CHD. However, despite these scientific advances, many of the molecular mechanisms underlying CHD remain unknown. Conclusion: Due to modern surgical techniques, the survival rate of affected infants is increasing. Deeper insight into the exact causes of this disease is crucial for diagnosing and identifying high-risk patients and improving preventive and therapeutic strategies for CHD. This review article aims to review and describe the latest discoveries regarding the influence of genetic and epigenetic factors in the development of coronary heart disease (CHD).

Exome sequencing uncovers promising candidate genes for foetal structural malformations

Background & objectives Prenatal ultrasonography in the first and second trimesters detects foetal structural anomalies in up to five per cent of pregnancies. These anomalies are often suspected to have a genetic cause. While conventional genetic tests such as karyotyping, fluorescent in situ hybridisation (FISH), and chromosomal microarray (CMA) have been used alongside whole-exome sequencing (WES), their combined diagnostic yield in malformed foetuses is limited to 40 per cent, leaving most cases undiagnosed. This study aimed to identify novel genetic factors linked to foetal structural malformations. Methods A total of 44 medically terminated foetuses were included in this study with severe structural malformations from a maternity hospital in the western part of India. We performed a comprehensive genetic analysis of products of conception (POC) employing karyotyping, FISH, CMA (750K resolution) and WES. Further, in cases with inconclusive genetic findings, we reanalysed the WES data using our in-house analysis pipeline and Exomiser (v13.2.1). Results Genetic anomalies identified among the 44 foetuses included trisomy 21 (n=4), trisomy 13 (n=3), and XXY mosaicism 47 (n=1) in 18.1 per cent (8 out of 44) of the cases. Further, CMA identified CNVs in 13.6 per cent (n=6) cases, of which five cases showed pathogenic CNVs. With the inclusion of WES, the diagnostic yield increased by 4.5 per cent. We reanalysed the WES data and identified six potential candidates, including RUNX2 (spinal dysraphism), PALLD (Arnold-Chiari malformation), KMT2D (Holoprosencephaly), FBN2 (structural heart and spine defects), CPLANE1 (Dandy-Walker malformation), and KMD1A (structural brain abnormality). Interpretation & conclusions This study summarises the findings of genetic evaluation of malformed foetuses in a low-resource setting, which caters to low-income groups of society. The candidate genes reported in this study offer scope for functional studies in relevant animal models to establish genotype-phenotype correlation.

Healthy euploid dizygotic twin birth after transfer of non-mosaic aneuploid embryos.

Healthy euploid dizygotic twin birth after transfer of non-mosaic aneuploid embryos.

Enhanced Recovery After Fetal Sequencing: A Perinatal Genomic Scoping Review of Exome / Genome Testing for Reproductive / Obstetric-MFM Providers to initiate Knowledge Translation following a Screening Ultrasound Identifying Fetal Anomalies.

This review of genomic perinatal opportunities and uses will provide counselling and personal genetic knowledge for improved patient care. M/M: This focused systematic analysis and review has used PUBMED keywords to identify genomic testing for ultrasound identified fetal anomaly (ies) that require diagnostic testing after an informed consent process. Multiple fetal anomalies, using TRIO sequencing processes, have a better diagnostic yield, with certain cohorts > 50%. For the single anatomic categories, skeletal, central nervous system, and renal systems, using WES fetal sequencing (most commonly) for a diagnostic result, have the larger incremental diagnostic yield over CMA. The phenotype-genotype (fetal-genomic result) consideration and use of the pES technology can be summarized using a SWOT analysis: strength (enhanced evaluation of fetal-neonatal genomic abnormalities not identified by standard chromosomal microarray and improved ethical care decisions); weakness (the understanding and complexity of genomic pathology and testing / the fiscal cost for professional time and the health system services); opportunity (an increased recognition of fetal genetic risk pathology [de novo or inherited carrier mutations] with improved understanding and knowledge translation of counselling for recurrence risk); threat (inability to provide a genetic diagnosis or interpret a variant of unknown significance or the discovery of incidental findings or unanticipated parental genomic diagnoses).

Uncovering genetic contributors to developmental delay and intellectual disability: a focus on CNVs in pediatric patients

BackgroundDevelopmental delay (DD) and intellectual disability (ID) are prevalent in children and often have genetic causes, particularly copy number variations (CNVs). Chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) are key diagnostic tools for identifying genetic contributions to these disorders. This study assesses the prevalence and clinical impact of CNVs in pediatric DD and ID patients.MethodsNinety-nine pediatric patients with DD or ID underwent CMA or WES. Of these, 82 received SNP array analysis, while 17 had WES. CNV pathogenicity was assessed using established databases and ACMG guidelines, with inheritance patterns determined where possible.ResultsAcross the 99 patients, 43 CNVs were identified in 40 individuals, with 32 classified as clinically significant, resulting in a diagnostic rate of 30.3%. These findings included 24 deletions (75%), 7 duplications (22%), and 1 instance of loss of heterozygosity (3%). Of the CNVs with known inheritance, 65.2% were de novo. Recurrent CNVs made up 36.4% of the total, especially in regions 15q11.2-q13.1, 16p11.2, and 22q11.2. Additionally, 11 CNVs were categorized as variants of uncertain significance (VOUS).ConclusionThis study supports CMA as an effective diagnostic tool for DD and ID, highlighting the importance of family-based CNV testing for genetic counseling. The findings emphasize the need for comprehensive genetic testing to improve diagnostic accuracy, with future multi-omics approaches potentially clarifying VOUS mechanisms and CNV variability in neurodevelopmental disorders.

Diagnostic Utility of Exome Data Reanalysis After In Silico Multi-Gene Panels or Clinical Exome Testing for Patients With Epilepsy and Developmental Delay/Intellectual Disability: A Retrospective Cohort Study.

Epilepsy is a relatively common condition with genetic factors contributing significantly to its etiology. Advances in next-generation sequencing have dramatically increased the number of known epilepsy genes, improving diagnostic capabilities and patient care. However, 50%-80% of epilepsy patients remain undiagnosed after genomic testing, which includes chromosomal microarray, multigene panels, and genome-wide sequencing. Reanalysis of existing exome sequencing data has shown promise in increasing diagnostic yield. In this study, we reanalyzed exome sequencing data from 87 individuals with unsolved epilepsy and developmental delay or intellectual disability in Ontario, Canada. Our approach combined clinical and translational research methodologies to identify genetic variants linked to epilepsy. We obtained a diagnostic yield of 14.9%, solving 13 participants, with 11 involving known genes and two novel gene discoveries. In addition, 11 potential diagnoses were identified, suggesting that further investigation could confirm additional diagnoses. Factors such as the inclusion of additional family data, new disease-gene associations, and technological advancements contributed to these findings. This study highlights the importance of reanalysis as a cost-effective and timely approach to improving diagnostic yield in epilepsy associated with neurodevelopmental delay.

Perinatal outcomes of resolved fetal cystic hygromas

Abstract IntroductionCystic hygroma is associated with additional fetal anomalies and genetic abnormalities. Although some cystic hygromas can progress to hydrops fetalis, some regress and resolve with advancing gestation. We aimed to describe the frequency with which cystic hygromas resolve, the prevalence and types of underlying genetic diagnoses, and the differences in perinatal outcomes for resolved cystic hygromas with and without genetic diagnoses.MethodsA retrospective cohort study (2013–2023) at a single tertiary medical center identified fetuses with cystic hygroma diagnosed in the first or second trimester that resolved on subsequent ultrasound imaging. Cystic hygromas were differentiated from increased nuchal translucency by Maternal‐Fetal Medicine physicians when a fluid‐filled lesion on the posterior neck and back was visualized to have septations or extend beyond the posterior nuchal region superiorly to the cranium or inferiorly. Ongoing pregnancies with prenatal and delivery data were included. We describe perinatal characteristics, genetic evaluations, and neonatal outcomes. Bivariate analyses compared outcomes among fetuses with and without genetic abnormalities. A p value < 0.05 was considered statistically significant.ResultsOf 284 fetal cystic hygromas, 59 (21%) resolved on subsequent imaging and resulted in live birth. The median gestational age at diagnosis was 12.0 weeks [interquartile range (IQR):11.1,12.3] and the latency to resolution was 5.6 weeks (IQR:4.6,8.0). A total of 28 (47%) fetuses had additional ultrasound anomalies, the most common of which were cardiac anomalies. Of 46 individuals who pursued diagnostic genetic testing (45 karyotypes, 30 chromosomal microarrays, and 20 gene panels), 15 (33%) had a genetic abnormality, including aneuploidy (n = 10), pathogenic deletion (n = 2), or single‐gene disorder (n = 3). Compared to fetuses with normal genetic testing, fetuses with genetic abnormalities were more likely to have a later gestational age at cystic hygroma diagnosis (12.3 vs. 11.6 weeks, p = 0.007) and resolution (20.1 vs. 17.3 weeks, p = 0.006) in addition to other structural ultrasound anomalies (67% vs. 13%, p = 0.001). A greater proportion of fetuses with resolved cystic hygromas and genetic abnormalities had growth restriction, an earlier delivery, longer neonatal stay, and neonatal complications compared to those with normal genetic evaluation.ConclusionThe frequency of cystic hygroma resolution in our cohort was 21%. A third of pregnancies who underwent diagnostic genetic testing were found to have an underlying genetic abnormality. Fetuses with genetic abnormalities were more likely to have other structural anomalies and obstetric complications compared to those with normal genetic testing. Providers should maintain a high index of suspicion for genetic conditions or associated anomalies in resolved cases and consider advanced testing even after apparent improvement on ultrasound.

Application of non-invasive prenatal testing for fetal chromosomal disorders in low-risk pregnancies: a follow-up study in central China.

To evaluate the performance and screening value of noninvasive prenatal testing (NIPT) in low-risk pregnancies. A retrospective analysis was conducted on 60193 low-risk pregnancies over the last 5years. Whole-genome sequencing of maternal plasma cell-free DNA was performed using next-generation sequencing. NIPT-positive results were confirmed using amniocentesis with karyotyping and/or copy number variation sequencing and chromosomal microarray analysis. Fetal outcomes were assessed using electronic medical records or telephone calls. Overall, 598 (0.99%) NIPT-positive cases were identified. The distribution of chromosomal abnormalities included sex chromosome aneuploidies (SCAs; 55.85%), rare autosomal aneuploidies (RAAs; 20.40%), copy number variations (CNVs; 11.20%), trisomy 21 (T21; 6.86%), trisomy 13 (T13; 4.01%), and trisomy 18 (T18; 1.67%). A total of 572 (95.65%) patients with NIPT-positive results underwent amniocentesis, and 55.77% (319/572) cases were confirmed. The positive predictive values (PPV) for T21, T18, T13, SCAs, RAAs, and CNVs were 87.50%, 60.00%, 34.78%, 58.97%, 32.50%, and 69.70%, respectively, and the PPV for the trisomy was higher than that for the X-monomer in SCAs. NIPT-positive results for RAAs were common in T8, T10, T16 and T20, but T16 was the most common true positive result, accounting for 33.33% (13/39) of the cases. The termination rates of true-positive pregnancies were 100% (T21, T18 and T13), 79.49% (RAAs), 67.39% (CNVs) and 78.07% (SCAs). This study highlights the importance of genome-wide screening based on NIPT in low-risk pregnancies. Prenatal screening by NIPT has a high sensitivity and PPV. Moreover, it can greatly reduce invasive procedures and birth defects.

Results of Chromosomal Microarray Need to Always Be Checked by (Molecular) Cytogenetics—Even If They Seem to Be Simple Deletions

Background/Objectives: Chromosome microarrays (CMAs) tend to be used as the first line test or as a test that does not require confirmation or verification by a second test. However, to understand the implications of a duplication or deletion for a family seeking genetic counseling, it is crucial to know the nature of the underlying chromosomal rearrangement. Here, we present seven cases with apparent isolated copy number loss, five of which showed unexpected complexity. Methods: Seven cases were investigated by CMA due to intellectual disability and/or dysmorphic features. Isolated deletions ranging in size from ~0.6 to ~21 Mb were found and referred for further characterization of the underlying chromosomal rearrangement. To elucidate the cases, fluorescence in situ hybridization was performed using locus-specific, whole and partial chromosome painting and/or multicolor banding. Results: Among the seven selected cases, there were five with unexpected complexity. Isolated deletions were actually evidence of chromoanasynthesis, ring chromosome formation, unbalanced translocation, or unbalanced insertion. Conclusions: These results clearly underscore that it seems reasonable to examine every case with a copy number variant—even if it appears to be “only” a simple partial deletion—using banding and/or molecular cytogenetic testing in order to make a qualified assessment of the situation and, on this basis, ensure sound genetic counseling.

Genome Sequencing Uncovers Additional Findings in Phelan-McDermid Syndrome.

Phelan-McDermid syndrome (PMS) is a genetic condition caused by deletions of chromosome 22q13.3 or pathogenic variants in the SHANK3 gene. Neurologic features typically include intellectual disability, autism spectrum disorder, hypotonia, and absent speech, though there is considerable variability even among individuals with the same molecular cause. This prospective study aimed to explore the utility of genome sequencing to identify additional molecular diagnoses that may contribute to variability in a cohort of patients with PMS. Twenty probands diagnosed with PMS (60% with a 22q13 deletion, 40% with a SHANK3 variant) underwent trio or duo genome sequencing and chromosomal microarray. This analysis identified a second molecular finding associated with a neurological condition in 3/20 participants. Molecular diagnoses related to neurological phenotypes included: (1) spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant (SMALED2A), (2) spastic paraplegia 7, and (3) 16p11.2 deletion syndrome. Five additional new molecular diagnoses were associated with a clinically actionable secondary or incidental finding. This exploratory study provides early evidence for the potential utility of expanded sequencing among individuals with PMS, even for those without phenotypic features outside of the expected range.

Outcome of fetuses with early increased nuchal translucency: systematic review and meta-analysis.

Nuchal translucency (NT) has been the mainstay of the first-trimester screening assessment for fetal aneuploidies. Although NT is typically measured between 11 and 14 weeks' gestation when fetal crown-rump length (CRL) is between 45 and 85 mm, recent studies suggest that fetuses with increased NT measured in the early first trimester of pregnancy are also at high risk of aneuploidy, genetic disorders or adverse pregnancy outcomes. The aim of this systematic review was to report the outcomes of fetuses with early increased NT before 11 weeks' gestation. MEDLINE, EMBASE and Cochrane databases were searched from inception to August 2024. The inclusion criteria were studies reporting the outcome of fetuses with increased NT, defined according to an absolute cut-off or percentile in the original publication, and a CRL < 45 mm. The primary outcome was a composite score of adverse pregnancy outcome, including the presence of either chromosomal, genetic or structural anomalies, or perinatal loss. The secondary outcomes explored were: resolution of increased NT at the 11-14-week scan; chromosomal anomaly; copy-number variant detected on chromosomal microarray; single-gene disorder detected on next-generation sequencing; structural anomaly; perinatal loss, defined as the occurrence of miscarriage or fetal loss; and termination of pregnancy. All outcomes were explored in the overall population of fetuses with early increased NT, according to the resolution or persistence of increased NT and according to different NT thickness (2.5-3.4 mm, 3.5-4.4 mm and ≥ 4.5 mm). Random effects meta-analysis of proportions was used to combine the data and results were reported as pooled proportions with 95% CI. Five studies (401 fetuses with CRL < 45 mm presenting with increased NT) were included in the systematic review and three of these (269 fetuses) were included in the meta-analysis. Composite adverse pregnancy outcome complicated 42.0% (95% CI, 18.5-67.6%) of pregnancies presenting with early increased NT. Chromosomal or genetic anomaly at either pre- or postnatal assessment was reported in 40.2% (95% CI, 12.8-71.5%) of cases. Structural anomaly was identified on ultrasound in 5.9% (95% CI, 3.4-9.1%) of fetuses with early increased NT, and perinatal loss occurred in 9.7% (95% CI, 6.4-13.5%) of cases. Of the fetuses presenting with increased NT in the early first trimester of pregnancy, 48.8% (95% CI, 30.6-67.1%) showed resolution of the increased NT at the 11-14-week scan, and the increased NT persisted in 51.2% (95% CI, 32.9-69.4%). Composite adverse pregnancy outcome occurred in 64.2% (95% CI, 51.8-75.6%) of fetuses in which increased NT was persistent at the 11-14-week scan and in 19.4% (95% CI, 8.8-33.0%) of those in which the increased NT resolved. Finally, when considering different cut-offs of NT thickness, adverse pregnancy outcome occurred in 31.9% (95% CI, 14.4-52.6%) of fetuses with NT between 2.5 and 3.4 mm, 50.4% (95% CI, 30.1-70.7%) of those with NT between 3.5 and 4.4 mm and 70.2% (95% CI, 32.0-94.9%) of those with NT ≥ 4.5 mm. Increased NT measured in the early first trimester of pregnancy is associated with an increased risk of adverse pregnancy outcome, chromosomal, genetic and structural anomalies, and perinatal loss, even in case of its resolution at the time of the 11-14-week scan. © 2025 International Society of Ultrasound in Obstetrics and Gynecology.

Placental mesenchymal dysplasia: A rare case report and literature review

Rationale:Placental mesenchymal dysplasia (PMD) is a rare placental disorder that poses diagnostic challenges and is often misdiagnosed as a trophoblastic tumor. While PMD is associated with fetal growth restriction, intrauterine fetal death, and pregnancy-induced hypertension, it does not involve malignant trophoblastic disease. Accurate diagnosis is crucial for optimizing maternal and fetal outcomes.Patient concerns:A 30-year-old female, gravida 3, para 1, with an uncomplicated medical history, presented with early pregnancy bleeding, which was managed with oral progesterone. Ultrasound at 13 weeks showed normal fetal morphology but a honeycomb-like placental appearance. At 23 weeks, ultrasound revealed fetal growth restriction, thickening of the placenta, and abnormal umbilical artery flow. Magnetic resonance imaging at 32 weeks confirmed abnormal placental masses.Diagnoses:Ultrasound, magnetic resonance imaging, and genetic testing (noninvasive prenatal testing, amniocentesis, and chromosomal microarray analysis) confirmed normal karyotype and identified distinctive placental abnormalities. Histopathological examination revealed edematous villi, fibromuscular hyperplasia, and amyloid-like protein deposits, consistent with PMD.Interventions:Prenatal care included enoxaparin sodium and management of fetal distress at 32 weeks with a cesarean section. Magnesium sulfate and dexamethasone were administered for fetal protection.Outcomes:Both mother and infant were healthy postpartum. The infant had favorable Apgar scores, and the patient’s blood pressure was managed with antihypertensive therapy. Maternal β-human chorionic gonadotropin levels remained normal throughout the pregnancy and postpartum.Lessons:PMD is an exceptionally rare placental disorder with a low incidence. It often presents with atypical ultrasound findings and can easily be misdiagnosed as a trophoblastic tumor, leading to unnecessary interventions. Diagnosing PMD is challenging, particularly in the absence of specific clinical symptoms. Clinicians must enhance awareness of this rare condition, prioritize early and accurate diagnosis through advanced imaging and histopathology, and differentiate PMD from other placental pathologies to ensure appropriate management and improve maternal-fetal outcomes.

Constitutional copy number amplifications: rare or under-evaluated? Revisiting a 25-year-old cold case.

We reanalyzed through a cytogenomics approach a case published 20 years ago, describing a girl with developmental delay and epilepsy. Karyotype and FISH analysis showed a de novo 2.3 Mb terminal inverted-duplication at 8q24.3. The interpretation was inconsistent with the absence of a more distal deletion as expected for distal inverted duplications, and it was inconceivable to highlight rearrangements smaller than 5-10 Mb at that time. Chromosomal microarray (CMA), optical genome mapping (OGM), and short-read whole genome sequencing (srWGS) identified a complex configuration at 8q24.3, which resembles events like chromoanasynthesis or DUP-TRP/INV-DUP (duplication-triplication/inverted-duplication), both characterized by clustered duplications and triplications, some of which are inverted. In the EBV-line genes located in the amplified regions were overexpressed. Despite a more precise definition of the imbalance, we were unable to provide a clear-cut explanation for the proband's clinical features.