Trisomy Research Articles

Analysis of chromosome test results of 24,175 miscarried fetuses in Japan from 2000 to 2021.

Fetal chromosome abnormalities, the most common cause of spontaneous abortion, were investigated pre-1980s. In recent years, chromosome testing has been outsourced to testing companies in Japan, and there have been few epidemiological studies of chromosome testing of miscarried fetuses on a nationwide scale. We analyzed the chromosome test data of SRL, Inc., one of the largest clinical laboratories that has collected tissue specimens of products of conception derived from miscarried fetuses from hospitals throughout Japan from 2000. We collected and analyzed 24,175 cases, among which 8,726 (36.1%) were normal chromosomes, 1,298 (5.4%) were sex chromosome abnormalities, 9,735 (40.3%) were autosomal trisomies, 73 (0.3%) were autosomal monosomies, 840 (3.5%) were ploidy, 512 (2.1%) were chromosome structural abnormalities, and 2,991 (12.4%) were mosaics. The frequency of autosomal trisomy increased at the older maternal ages. By chromosome number, trisomies 22, 16, 21, and 15 were associated with advanced maternal age, but trisomies 13, 14, and 18 were not associated with advanced maternal age. The presence or absence of this maternal age effect was correlated with the chromosome segregation being due to maternal meiosis I or meiosis II. For the sex ratios of the fetuses, we focused on trisomies 22, 21, 18, 16, 15, 14, and 13, and found that only trisomy 16 was significantly more frequently seen in female fetuses. The findings of this study provide insights into the basic understanding of miscarriage and will be useful in counseling and medical education.

Prevalence of Autosomal Monosomy and Trisomy Estimated Using Single Nucleotide Polymorphism Genotype Intensity Chip Information in a Large Population of Juvenile Dairy and Beef Cattle.

Aneuploidy, a genetic condition characterised by the deletion (monosomy) or duplication (trisomy) of a chromosome, has been extensively studied in humans, particularly in the context of trisomy on chromosome 21, also known as Down syndrome. Research on autosomal aneuploidy in live-born cattle has been limited to case reports, resulting in a lack of prevalence estimates of aneuploidy in cattle. Furthermore, the viability or lethality of aneuploidy on specific autosomes in cattle has not been well documented. The objective of this study was to estimate the prevalence of autosomal aneuploidy in a large population of new-born and juvenile beef and dairy cattle using single nucleotide polymorphism (SNP) chip genotype intensity data. Of the population of 779,138 cattle genotyped when younger than 15 months of age, 139 cattle (i.e., 0.017%) were diagnosed with one case of autosomal trisomy. Trisomy in only 10 different autosomes were detected (BTA 4, 6, 12, 15, 20, 24, 26, 27, 28 and 29) albeit the one case of trisomy detected on Bos taurus autosome (BTA) 4 was in an additional population of 341,927 cattle that were genotyped at > 15 months of age and was therefore excluded from prevalence estimates to minimise bias. The prevalence of trisomy per chromosome was generally inversely related to the length of the chromosome. Although the number of affected individuals was few, there was no evidence of differences in prevalence by breed, inbreeding level or parental age. The parental origin of the detected cases of trisomy was maternal for 92% of the cases. No cases of monosomy were detected despite the large dataset, which included calves genotyped at birth, indicating the potential lethal nature of monosomy in cattle. Cytogenetic testing was used to verify three of the animals with detected autosomal trisomy who were still alive. Eighteen of the 139 animals identified with autosomal trisomy were recorded as being stillborn, resulting in a prevalence of autosomal aneuploidy in live-born cattle of 0.015%. Of the 121 live-born cattle with autosomal trisomy, a total of 68 died on farm at, on average (standard deviation), 6.8 (8.7) months of age. All animals with autosomal trisomy on BTA 6, 12, 15, 20 or 24 were either stillborn or died on farm within 15 days of birth. This study is the first report of trisomy on BTA 4, 6, 15, 20 and 27 in live-born cattle, as well as the first to document fertile cows with trisomy on BTA 4, 27 or 28. Given that genotype intensity SNP data from SNP-chips are readily available, identifying animals affected with autosomal aneuploidy as well as quantifying and monitoring the incidence can be easily undertaken.

Autophagy is a promising process for linking inflammation and redox homeostasis in Down syndrome.

Trisomy 21, characterized by the presence of an additional chromosome 21, leads to a set of clinical features commonly referred to as Down syndrome (DS). The pathological phenotypes observed in DS are caused by a combination of factors, such as mitochondrial dysfunction, neuroinflammation, oxidative stress, disrupted metabolic patterns, and changes in protein homeostasis and signal transduction, and these factors collectively induce neurological alterations. In DS, the triplication of chromosome 21 and the micronuclei arising from the missegregation of chromosomes are closely associated with inflammation and the development of redox imbalance. Autophagy, an essential biological process that affects cellular homeostasis, is a powerful tool to facilitate the degradation of redundant or dysfunctional cytoplasmic components, thereby enabling the recycling of their constituents. Targeting the autophagy process has been suggested as a promising method to balance intracellular inflammation and oxidative stress and improve mitochondrial dysfunction. In this review, we summarize the role of autophagy in regulating inflammation and redox homeostasis in DS and discuss their crosslinks. A comprehensive elucidation of the roles of autophagy in DS offers novel insights for the development of therapeutic strategies aimed at aneuploidy-associated diseases.

Reversal of neurodevelopmental impairment and cognitive enhancement by pharmacological intervention with the polyphenol polydatin in a Down syndrome model

Intellectual disability (ID) is the unavoidable hallmark of Down syndrome (DS), a genetic condition due to triplication of chromosome 21. ID in DS is largely attributable to neurogenesis and dendritogenesis alterations taking place in the prenatal/neonatal period, the most critical time window for brain development. There are currently no treatments for ID in DS. Considering the timeline of brain development, treatment aimed at improving the neurological phenotypes of DS should be initiated as early as possible and use safe agents. The goal of this study was to establish whether it is possible to improve DS-linked neurodevelopmental defects through early treatment with polydatin, a natural polyphenol. We used the Ts65Dn mouse model of DS and focused on the hippocampus, a brain region fundamental for long-term memory. We found that in Ts65Dn mice of both sexes treated with polydatin from postnatal (P) day 3 to P15 there was full restoration of neurogenesis, neuron number, and dendritic development. These effects were accompanied by normalization of Cyclin D1 and DSCAM levels, which may account for the rescue of neurogenesis and dendritogenesis, respectively. Importantly, in Ts65Dn mice treated with polydatin from P3 to adolescence (∼P50) there was full restoration of hippocampus-dependent memory, indicating a pro-cognitive outcome of treatment. No adverse effects were observed on the body and brain weight. The efficacy and safety of polydatin in a model of DS prospect the possibility of its use during early life stages for amelioration of DS-linked neurodevelopmental alterations.

Parent Narratives Provide Perspectives on the Experience of Care in Trisomy 18.

Trisomy 18 syndrome, also known as Edwards syndrome, is the second most common autosomal chromosome syndrome after Down syndrome. Trisomy 18 is a serious medical disorder due to the increased occurrence of structural defects, the high neonatal and infant mortality, and the disabilities observed in older children. Interventions, including cardiac surgery, remain controversial, and the traditional approach is to pursue pure comfort care. While the medical challenges have been well-characterized, there are scant data on the parental views and perspective of the lived experience of rearing a child with trisomy 18. Knowledge of the parental viewpoints can help clinicians guide families through decision-making. Our aim was to identify parents' perspectives by analyzing a series of narratives. In this qualitative study, we collected 46 parent narratives at the 2015 and 2016 conferences of the Support Organization for Trisomy 18 & 13 (SOFT). The participants were asked to "Tell us a story about your experience." Inductive content analysis and close reading were used to identify themes from the stories. Dedoose, a web-based application to analyze qualitative data, was used to code themes more systematically. Of the identified themes, the most common included Impact of trisomy 18 diagnosis and Surpassing expectations. Other themes included Support from professionals, A child, not a diagnosis, and Trust/lack of trust. We examined the voice and the perspectives of the parents in their challenges in caring for their children with this life-limiting condition. The exploration of the themes can ideally guide clinicians in their approach to the counseling and care of the child in a shared decision-making approach.

Combined first-trimester screening and invasive diagnostics for atypical chromosomal aberrations: Danish nationwide study of prenatal profiles and detection compared with NIPT.

Our aim was to examine the prenatal profiles of pregnancies affected by an atypical chromosomal aberration, focusing on pathogenic copy-number variants (pCNVs). We also wanted to quantify the performance of combined first-trimester screening (cFTS) and a second-trimester anomaly scan in detecting these aberrations. Finally, we aimed to estimate the consequences of a policy of using non-invasive prenatal testing (NIPT) rather than invasive testing with chromosomal microarray analysis (CMA) to manage pregnancies identified as high risk by cFTS. This was a retrospective review of the Danish Fetal Medicine Database of all pregnant women who underwent cFTS and a risk assessment for trisomy 21 between 1 January 2008 and 31 December 2018. Chromosomal aberrations diagnosed prenatally, postnatally or from fetal tissue following pregnancy loss or termination of pregnancy were identified. Chromosomal aberrations were grouped into one of six categories: triploidy; common trisomy (13, 18 or 21); monosomy X; other sex-chromosome aberration (SCA); pCNV; and rare autosomal trisomy (RAT) or mosaicism. The prevalence of each aberration category was stratified by the individual cFTS markers and trisomy 21 risk estimate, and the size of each pCNV diagnosed by CMA was calculated. We retrieved data on 565 708 pregnancies, of which 3982 (0.70%) were diagnosed with a fetal chromosomal aberration. cFTS identified 87% of the common trisomies, but it also performed well in identifying triploidies (86%), monosomy X (92%), atypical SCAs (58%) and RATs or mosaicisms (70%). pCNVs comprised 27% (n = 1091) of the chromosomal aberrations diagnosed overall, and the prevalence increased during the study period, as prenatal CMA was increasingly being performed. In pregnancies with a maternal age < 30 years, nuchal translucency (NT) thickness ≤ 95th centile, pregnancy-associated plasma protein-A (PAPP-A) ≥ 1 multiple of the median, or trisomy 21 risk of ≤ 1 in 1000, the prevalence of pCNVs exceeded significantly the prevalence of trisomies 21, 18 and 13. Pregnancies affected by a pCNV had significantly increased NT and decreased levels of the maternal biomarkers PAPP-A and β-human chorionic gonadotropin compared with unaffected pregnancies. However, only 23% of these pregnancies screened positive on cFTS and 51% of pCNVs were not detected until after birth. Among high-risk pregnancies, pCNVs comprised 14% of diagnosed aberrations, and when other atypical aberrations were considered, conventional NIPT (screening for trisomies 21, 18 and 13 and monosomy X) would miss 27% of all pathogenic aberrations diagnosed from invasive testing following a high-risk cFTS result. Thus, 1 in 26 pregnancies at high risk following cFTS would be affected by a chromosomal aberration despite a normal result from conventional NIPT. In a contingent screening model using NIPT for the 'intermediate'-risk group (trisomy 21 risk of 1 in 100-299), 50% of the aberrations would be missed. In our cohort, 79% of the pCNVs diagnosed were < 5Mb and therefore not detectable using current forms of 'genome-wide' NIPT. As a by-product of screening for trisomies 21, 18 and 13, most triploidies and the majority of atypical SCAs, RATs and mosaicisms are detected before birth. However, only 23% of pCNVs are associated with a high-risk result according to cFTS and only half are diagnosed before birth. Replacing invasive testing with NIPT for high-risk pregnancies would substantially decrease the first-trimester detection of pathogenic chromosomal anomalies. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Placental mosaicism for autosomal trisomies: comprehensive follow-up of 528 Danish cases (1983–2021)

BackgroundMosaicism, characterized by the presence of two or more chromosomally distinct cell lines, is detected in 2% to 4% of chorionic villus samples (CVSs). In these cases, the aberration may be confined to the placenta or additionally present in the fetus. Fetal involvement may manifest as fetal malformations, while confined placental mosaicism (CPM) poses risks such as preterm birth and low birth weight. Differentiating between true fetal mosaicism and CPM at the time of the chorionic villus sampling is challenging and requires follow-up by an amniocentesis and ultrasonography. ObjectiveTo estimate the risk of fetal involvement or adverse pregnancy outcomes for specific chromosomes after detecting mosaicism for an autosomal trisomy in a CVS and identify high (red), intermediate (yellow), and low (green) risk chromosomes. Further, to explore possible associations with level of mosaicism and screening parameters. Study DesignA retrospective descriptive study of all singleton pregnancies with mosaicism detected in CVSs from 1983 to 2021 identified in the Danish Cytogenetic Central Registry and the Danish Fetal Medicine Database. ResultsOf 90,973 CVSs, 528 cases had mosaicism involving an autosomal trisomy and where genetic follow-up had been performed. The overall risk of fetal involvement was 13% (69/528) with extensive variations depending on which chromosome was involved (eg, trisomy 7: 0% [0/55] or trisomy 21: 46% [19/41]). Higher levels of mosaicism in the CVS suggested fetal involvement as mean mosaic level was 55% in true fetal mosaics vs 28% in cases confined to the placenta (P=.0002). In cases with CPM (459/528), the risk of delivering small-for-gestational-age neonates was 14% (48/341). The risk of preterm birth (before 37 weeks) was 15% (51/343). The collective risk of adverse outcome was 22% (76/343) in pregnancies that continued and where information on birth weight and gestational age at birth was available. Adverse outcomes varied substantially between chromosomes. Also, multiple-of-the-median (MoM) values of pregnancy-associated plasma protein A was predictive of these issues as it was significantly lower in cases with adverse outcome compared to cases with a normal outcome (small for gestational age: 0.23 MoM vs 0.47 MoM, P<.0001) or preterm birth: 0.25 MoM vs 0.47 MoM, P<.0001). After the introduction of combined first-trimester screening (cFTS) in 2004, the detection of cases with fetal involvement seemed to increase as the risk before 2004 was 9% (16/174) compared to 15% (53/354) after 2004 (risk ratio: 1.7 [95% CI: 1.0; 2.8]). The risk of adverse outcome in CPM pregnancies increased from 16% (22/139) before 2004 to 27% (55/204) after 2004 (risk ratio 1.7 [95% CI: 1.1; 2.7]). ConclusionIntroducing cFTS increased the detection of placental mosaicism with fetal involvement and CPM with adverse outcome. In cases of mosaicism in CVSs, the risk of fetal involvement and adverse outcomes varied considerably between chromosomes. Importantly, adverse outcomes were seen in CPM for many trisomies besides trisomy 16.

Performance evaluation of noninvasive prenatal testing on 24 chromosomes in a cohort of 118,969 pregnant women in Sichuan, China.

This study aimed to comprehensively analyze the detection capacity of non-invasive prenatal testing (NIPT) for chromosomal abnormalities of all 24 chromosomes, as well as high-risk indications for pregnancy and the fetal fraction, in a large cohort. We retrospectively enrolled 118,969 pregnant women who underwent NIPT at Sichuan Provincial Maternity and Child Health Care Hospital from March 2019 to June 2022. The sensitivity, specificity, positive predictive value, negative predictive value, and positive chromosomal abnormality rate were calculated. The fetal fraction based on gestational age, maternal body mass index, and number was examined. NIPT demonstrated > 99% sensitivity and specificity for almost all of the common trisomies (T21, T18, and T13), sex chromosomal aneuploidies, rare autosomal trisomies, and microdeletion/microduplication syndromes. Positive predictive values varied from 12.0% to 89.6%. Advanced maternal age was associated with an increased risk of three major aneuploidies. The fetal fraction was positively correlated with gestational age and negatively correlated with the maternal body mass index. NIPT can be used to effectively screen for chromosomal abnormalities across all 24 chromosomes. Advanced maternal age is a risk factor for high-risk pregnancy, and careful consideration of the fetal fraction is essential during NIPT.

Unusual Maternal and Fetal Findings With Cell-Free DNA Screening.

With advances in prenatal cell-free DNA (cfDNA) technology, the information available with cfDNA continues to expand beyond the common fetal aneuploidies such as trisomies 21, 18, and 13. Due to the admixture of maternal and fetal/placental DNA, prenatal cfDNA remains a screening test with the possibility of false-positive and false-negative results. This review aims to summarize unusual incidental maternal and fetal genomic abnormalities detectable by cfDNA and to provide anticipatory guidance regarding management. Of 140 articles identified with keywords such as "incidental" and "discordant" cfDNA, 55 original research articles, review articles, case series, and societal guidelines were reviewed. Prenatal cfDNA may incidentally identify a spectrum of maternal genomic abnormalities such as malignancy, mosaicism, and copy number variants. When discordant with fetal diagnosis, these cases require additional investigation with maternal genetic testing and follow-up evaluation. Such incidental fetal/placental abnormalities may include rare autosomal trisomies, uniparental disomy, and triploidy. Further evaluation of fetal/placental abnormalities can be pursued with a combination of ultrasound and prenatal diagnosis with chorionic villous sampling and/or amniocentesis. Societal guidelines do not currently recommend cfDNA screening for rare autosomal trisomies, microdeletions, or copy number variants, and some experts suggest that sex chromosome screening should be opted in after counseling. Knowledge about possible incidental findings with prenatal cfDNA is needed to inform pretest and posttest counseling with appropriate follow-up evaluation. As cfDNA technology has advanced to include genome-wide findings, it is important for clinicians, genetic counselors, and societal guidelines to acknowledge the spectrum of possible results outside of the traditional and sex chromosome aneuploidies.

Prenatal Diagnosis of Cleft Lip and Palate: A Retrospective Study.

Cleft lip and/or palate are prevalent congenital anomalies. Early and accurate diagnosis allows proper case management. The Objective: This retrospective cohort study aimed to investigate the association between cleft lip and palate and other congenital anomalies. Methods: This study analyzed 17 pregnancies prenatally diagnosed with cleft lip and palate. The investigations consisted of ultrasound examination, fetal karyotyping through amniocentesis, and family tree analysis. In the presence of an abnormal fetal karyotype, the parental karyotype was also indicated. Results: Of the 17 cases identified, 9 (52.94%) were syndromic and 8 (47.06%) were non-syndromic. The genetic syndromes identified in association with cleft lip and palate in this study included translocation syndrome (one case), Patau syndrome, trisomy 13 (seven cases), and Edwards syndrome, mosaic trisomy 18 (one case). Conclusions: A comprehensive approach ensures a thorough assessment and accurate diagnosis. Early detection and a multidisciplinary approach allow appropriate case management.

Miscarriages after Natural Conception &amp; IVF: Comparative Study of Genetic Analysis of Products of Conception

Assisted reproductive technologies (ART), including in vitro fertilization (IVF), are modern medical technologies widely used in developed countries. A frequent complication of pregnancy resulting from ART is miscarriage. The leading cause of miscarriage, both sporadic and recurrent, is chromosomal abnormalities (CA) of the embryo. To compare the frequency and structure of chromosomal abnormalities (CA) of the embryo during miscarriages after IVF and natural conception. Retrospective cohort comparative study. The study, conducted in 2018-2022, included 1,000 products of conception (POCs) samples from patients with miscarriage. The study participants were divided into 2 groups depending on the origin of pregnancy: group 1 – women whose pregnancy occurred naturally (n = 862), group 2 – women whose pregnancy occurred as a result of in vitro fertilization (IVF) (n = 138). Miscarriage was confirmed by ultrasound performed at 6-10 weeks of pregnancy. A genetic study of POCs was carried out using chromosomal microarray analysis (CMA). In total, CA was detected in 580 samples (58%), and a normal molecular karyotype was determined in 420 (42%). CAs in abortive material during pregnancy loss are detected with a frequency of 59.05% in cases of natural conception and with a frequency of 51.05% in pregnancies resulting from IVF (p = 0.093). There were no statistically significant differences in the frequency and structure of CA in the study groups. Autosomal trisomies were most often detected. In our study, among all autosomal trisomies, the most common were trisomy 16, trisomy 22 and trisomy 15. Among the sex chromosome abnormalities, monosomy X was most often detected - in total, it was determined in 66 (6.6%) samples, which significantly exceeds the frequency of monosomy X among live births. Only in 0.2-0.3% of cases, when the embryo has monosomy X, pregnancy progresses and ends in a live birth. Copy number variations (CNVs) were often detected - a total of 52 (5.2%) samples with different CNVs, respectively 46 (5.3%) and 6 (4.3%) in groups 1 and 2. Detection of such abnormality is critically important, as it can be the result of carriage of a balanced CAs in one of the parents, which significantly increases the risk of miscarriage in the future. In pregnancies resulting from IVF, mosaicism in abortive material was more common, but the differences were not statistically significant. In group 1, mosaicism was detected in 66 (7.6%) cases and in group 2 - 13 (9.4%) cases. The IVF procedure does not increase the risk of CA in the embryo but also does not significantly reduce it. Considering the high frequency of CA in miscarriage, persons referred for IVF and with a history of idiopathic recurrent pregnancy loss should be informed about the possibility of PGT.

Down syndrome and DYRK1A overexpression: relationships and future therapeutic directions.

Down syndrome is a genetic-based disorder that results from the triplication of chromosome 21, leading to an overexpression of many triplicated genes, including the gene encoding Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A). This protein has been observed to regulate numerous cellular processes, including cell proliferation, cell functioning, differentiation, and apoptosis. Consequently, an overexpression of DYRK1A has been reported to result in cognitive impairment, a key phenotype of individuals with Down syndrome. Therefore, downregulating DYRK1A has been explored as a potential therapeutic strategy for Down syndrome, with promising results observed from in vivo mouse models and human clinical trials that administered epigallocatechin gallate. Current DYRK1A inhibitors target the protein function directly, which tends to exhibit low specificity and selectivity, making them unfeasible for clinical or research purposes. On the other hand, antisense oligonucleotides (ASOs) offer a more selective therapeutic strategy to downregulate DYRK1A expression at the gene transcript level. Advances in ASO research have led to the discovery of numerous chemical modifications that increase ASO potency, specificity, and stability. Recently, several ASOs have been approved by the U.S. Food and Drug Administration to address neuromuscular and neurological conditions, laying the foundation for future ASO therapeutics. The limitations of ASOs, including their high production cost and difficulty delivering to target tissues can be overcome by further advances in ASO design. DYRK1A targeted ASOs could be a viable therapeutic approach to improve the quality of life for individuals with Down syndrome and their families.

Unusual anatomical variants of infrahyoid muscles - case report.

Anatomical anomalies of neck muscles are rarely observed and usually comprise variations of digastric and omohyoid muscles. Neck muscles' abnormalities might be correlated with embryological development and are observed in individuals with aneuploidies such as Edward's syndrome (18-trisomy) or Down syndrome (21-trisomy). Some infrahyoid muscles are important landmarks during surgery, therefore their anatomical variations of these muscles are related to higher risk of surgical complications. Herein, we present a rare case of infrahyoid muscles anomalies found during routine dissection of male cadaver. Redundant muscle bellies of sternohyoid muscle (sternohyoid azygos muscle), presence of levator glandulae thyroideae and also one hypoplastic superior belly of the omohyoid muscle were observed. Presence of muscle fibers within found structures was confirmed using Masson's trichrome staining method.

Prenatal and Postnatal Diagnosis and Genetic Background of Corpus Callosum Malformations and Neonatal Follow-Up.

The corpus callosum is one of the five main cerebral commissures. It is key to combining sensory and motor functions. Its structure can be pathological (dysgenesis) or completely absent (agenesis). The corpus callosum dys- or agenesis is a rare disease (1:4000 live births), but it can have serious mental effects. In our study, we processed the data of 64 pregnant women. They attended a prenatal diagnostic center and genetic counseling from 2005 to 2019 at the Department of Obstetrics and Gynecology at Semmelweis University. The pregnancies had the following outcomes: 52 ended in delivery, 1 in spontaneous abortion, and 11 in termination of pregnancy (TOP) cases (n = 64). The average time of detection with imaging tests was 25.24 gestational weeks. In 16 cases, prenatal magnetic resonance imaging (MRI) was performed. If the abnormality was detected before the 20th week, a genetic test was performed on an amniotic fluid sample obtained from a genetic amniocentesis. Karyotyping and cytogenetic tests were performed in 15 of the investigated cases. Karyotyping gave normal results in three cases (46,XX or XY). In one of these cases, postnatally chromosomal microarray (CMA) was later performed, which confirmed Aicardi syndrome (3q21.3-21.1 microdeletion). In one case, postnatally, the test found Wiedemann-Rautenstrauch syndrome. In other cases, it found X ring, Di George syndrome, 46,XY,del(13q)(q13q22) and 46,XX,del(5p)(p13) (Cri-du-chat syndrome). Edwards syndrome was diagnosed in six cases, and Patau syndrome in one case. We found that corpus callosum abnormalities are often linked to chromosomal problems. We recommend that a cytogenetic test be performed in all cases to rule out inherited diseases. Also, the long-term outcome does not just depend on the disease's severity and the associated other conditions, and hence proper follow-up and early development are also key. For this reason, close teamwork between neonatology, developmental neurology, and pediatric surgery is vital.

Occurrence of mosaic Down syndrome and prevalence of co-occurring conditions in Medicaid enrolled adults, 2016-2019.

Mosaic Down syndrome is a triplication of chromosome 21 in some but not all cells. Little is known about the epidemiology of mosaic Down syndrome. We described prevalence of mosaic Down syndrome and the co-occurrence of common chronic conditions in 94,533 Medicaid enrolled adults with any Down syndrome enrolled from 2016 to 2019. We identified mosaic Down syndrome using the International Classification of Diseases and Related Health Problems, tenth edition code for mosaic Down syndrome and compared to those with nonmosaic Down syndrome codes. We identified chronic conditions using established algorithms and compared prevalence by mosaicism. In total, 1966 (2.08%) had claims for mosaic Down syndrome. Mosaicism did not differ by sex or race/ethnicity with similar age distributions. Individuals with mosaicism were more likely to present with autism (13.9% vs. 9.6%) and attention deficit hyperactivity disorder (17.7% vs. 14.0%) compared to individuals without mosaicism. In total, 22.3% of those with mosaic Down syndrome and 21.5% of those without mosaicism had claims for Alzheimer's dementia (Prevalence difference: 0.8; 95% Confidence interval: -1.0, 2.8). The mosaic group had 1.19 times the hazard of Alzheimer's dementia compared to the nonmosaic group (95% CI: 1.0, 1.3). Mosaicism may be associated with a higher susceptibility to certain neurodevelopmental and neurodegenerative conditions, including Alzheimer's dementia. Our findings challenge previous assumptions about its protective effects in Down syndrome. Further research is necessary to explore these associations in greater depth.

Down Syndrome and Autoimmune Disease.

Down syndrome is the most common genetic cause of intellectual disability and has previously been associated with a variety of autoimmune disorders affecting multiple organ systems. The high prevalence of autoimmune disease, in conjunction with other inflammatory and infectious diseases, in this population suggests an intrinsic immune dysregulation associated with triplication of chromosome 21. Emerging data on the role of chromosome 21 in interferon activation, cytokine production, and activation of B-cell mediated autoimmunity are emerging hypotheses that may explain the elevated prevalence of autoimmune thyroid disease, celiac disease, type I diabetes, autoimmune skin disease, and a variety of autoimmune neurologic conditions. As the life expectancy for individuals with Down syndrome increases, knowledge of the epidemiology, clinical features, management and underlying causes of these conditions will become increasingly important. Disorders such as Hashimoto's thyroiditis are prevalent in between 13 and 34% of individuals with Down syndrome but only 3% of the neurotypical population, a pattern similarly recognized in individuals with Celiac Disease (5.8% v 0.5-2%), alopecia areata (27.7% v. 2%), and vitiligo (4.4% v. 0.05-1.55%), respectively. Given the chronicity of autoimmune conditions, early identification and management can significantly impact the quality of life of individuals with Down syndrome. This comprehensive review will highlight common clinical autoimmune conditions observed in individuals with Down syndrome and explore our current understanding of the mechanisms of disease in this population.

Cell-free DNA screening for common autosomal trisomies using rolling-circle replication in twin pregnancies.

To evaluate the performance of prenatal screening for common autosomal trisomies in twin pregnancies through the use of rolling-circle replication (RCR)-cfDNA as a first-tier test. Prospective multicenter study. Women who underwent prenatal screening for trisomy (T) 21, 18 and 13 between January 2019 and March 2022 in twin pregnancies were included. Patients were included in two centers. The primary endpoint was the rate of no-call results in women who received prenatal screening for common autosomal trisomies by RCR-cfDNA at the first attempt, compared to that in prospectively collected samples from 16,382 singleton pregnancies. The secondary endpoints were the performance indices of the RCR-cfDNA. 862 twin pregnancies underwent screening for T21, T18 and T13 by RCR-cfDNA testing at 10-33weeks' gestation. The RCR-cfDNA tests provided a no-call result from the first sample obtained from the patients in 107 (0.7%) singleton and 17 (2.0%) twin pregnancies. Multivariable regression analysis demonstrated that significant independent predictors of test failure were twin pregnancy and in vitro fertilization conception. All cases of T21 (n=20/862; 2.3%), T18 (n=4/862; 0.5%) and T13 (n=1/862; 0.1%) were correctly detected by RCR-cfDNA (respectively, 20, 4 and 1 cases). Sensitivity was 100% (95% CI, 83.1%-100%), 100% (95% CI 39.8%-100%) and 100% (95% CI 2.5%-100%) for T21, T18 and T13, respectively, in twin pregnancies. The RCR-cfDNA test appears to have good accuracy with a low rate of no-call results in a cohort of twin pregnancies for the detection of the most frequent autosomal trisomies.

Disparities in integrating non-invasive prenatal testing into antenatal healthcare in Australia: a survey of healthcare professionals

BackgroundNon-invasive prenatal testing (NIPT) has been clinically available in Australia on a user-pays basis since 2012. There are numerous providers, with available tests ranging from targeted NIPT (only trisomies 21, 18, and 13 +/- sex chromosome aneuploidy) to genome-wide NIPT. While NIPT is being implemented in the public health care systems of other countries, in Australia, the implementation of NIPT has proceeded without public funding. The aim of this study was to investigate how NIPT has been integrated into antenatal care across Australia and reveal the successes and challenges in its implementation in this context.MethodsAn anonymous online survey was conducted from September to October 2022. Invitations to participate were sent to healthcare professionals (HCPs) involved in the provision of NIPT in Australia through professional society mailing lists and networks. Participants were asked questions on their knowledge of NIPT, delivery of NIPT, and post-test management of results.ResultsA total of 475 HCPs responded, comprising 232 (48.8%) obstetricians, 167 (35.2%) general practitioners, 32 (6.7%) midwives, and 44 (9.3%) genetic specialists. NIPT was most commonly offered as a first-tier test, with most HCPs (n = 279; 60.3%) offering it to patients as a choice between NIPT and combined first-trimester screening. Fifty-three percent (n = 245) of respondents always offered patients a choice between NIPT for the common autosomal trisomies and expanded (including genome-wide) NIPT. This choice was understood as supporting patient autonomy and informed consent. Cost was seen as a major barrier to access to NIPT, for both targeted and expanded tests. Equitable access, increasing time demands on HCPs, and staying up to date with advances were frequently reported as major challenges in delivering NIPT.ConclusionsOur findings demonstrate substantial variation in the clinical implementation of NIPT in Australia, including in the offers of expanded screening options. After a decade of clinical use, Australian clinicians still report ongoing challenges in the clinical and equitable provision of NIPT.

Holoprosencephaly: The Disease and Its Related Disabilities

AbstractHoloprosencephaly (HPE), the most prevalent developmental anomaly affecting the forebrain in humans, occurs in ∼1 in 16,000 liveborn neonates, with an incidence reaching 1 in 250 in conceptuses. This condition is distributed worldwide. HPE is etiologically heterogeneous, and its pathogenesis is variable. Environmental, teratogenic, genetic, or metabolic factors can contribute to the development of HPE. Notably, maternal insulin-dependent diabetes mellitus and maternal alcoholism are among the primary causative factors. HPE may be linked to various well-defined multiple malformation syndromes characterized by a normal karyotype, such as Smith–Lemli–Opitz's, Pallister–Hall's, or velocardiofacial syndrome. Alternatively, it can be associated with chromosomal abnormalities. (i.e., Patau's syndrome and, less frequently, Edwards' syndrome or Down's syndrome). The major genes implicated in HPE are SHH, ZIC2, SIX3, and TGIF. The range of HPE is extensive, covering diverse neuropathological phenotypes of varying severity. Three classical types of HPE can be distinguished in increasing order of severity: lobar HPE, characterized by separated right and left ventricles with some continuity across the frontal cortex; semilobar HPE, featuring a partial separation; and the most severe form, alobar HPE, where there is a single brain ventricle and the absence of an interhemispheric fissure. Additionally, there are other variations of HPE, ranging in severity, including the less severe interhemispheric median HPE (also known as middle interhemispheric variant). The phenotypic spectrum of HPE is highly extensive, encompassing severe cerebral malformations to microforms. Children with HPE often encounter numerous medical challenges; among them neurological disorders, craniofacial malformations, endocrine disorders, oral and motor dysfunction, and dysfunction of the autonomic nervous system. Neurologic problems, such as cerebral palsy and seizures, are common. The diagnosis of HPE is typically made prenatally, relying primarily on ultrasound and magnetic resonance imaging examinations. The prognosis for individuals with HPE is largely dependent on its underlying causes. Those with cytogenetic abnormalities, in particular, face a significantly poorer prognosis, with only 2% surviving beyond 1 year.

A clinical case of trisomy on chromosome 18 (Edwards Syndrome)

Edwards syndrome (trisomy on chromosome 18) is a genetic disorder caused by the presence of an extra copy of the eighteenth chromosome in humans. It is the second most common chromosomal disorder after Down syndrome. The frequency of Edwards syndrome among newborns is 1:5000–1:7000. The ratio of boys to girls is 1:3. The karyotype of sick girls and boys is 47, XX+18, 47, XY+18, and 47, XY+18, respectively. Patients are born with low birth weight (about 2 kg), they have delayed growth and development, mental retardation, wide fontanels at birth and open cranial sutures, the thorax is wider and shorter than normal, the mandible and mouth opening are small. The eye slits are narrow and short, the auditory orifices are deformed and sometimes absent. There are defects of the heart and large vessels, hypoplasia of the cerebellum and corpus callosum. 5–10% survive to the age of one year, all survivors are profound oligophrenics [1–4].