Trisomy Research Articles

Comparison of amyloid accumulation between Down syndrome and autosomal‐dominant Alzheimer disease

AbstractBackgroundGiven the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development.MethodWe assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer’s Biomarker Consortium‐Down Syndrome (ABC‐DS) and 265 mutation‐carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated‐years‐to‐symptom‐onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC‐DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40.ResultThe relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ ‐23 but was not elevated in DS until EYO ≥ ‐15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5).ConclusionThese results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5‐10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy.

Comparison of amyloid accumulation between Down syndrome and autosomal‐dominant Alzheimer disease

AbstractBackgroundGiven the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development.MethodWe assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer’s Biomarker Consortium‐Down Syndrome (ABC‐DS) and 265 mutation‐carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated‐years‐to‐symptom‐onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC‐DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40.ResultThe relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ ‐23 but was not elevated in DS until EYO ≥ ‐15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5).ConclusionThese results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5‐10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy.

Positive predictive values and outcomes for uninformative cell-free DNA tests: An Italian multicentric Cytogenetic and cytogenomic Audit of diagnOstic testing (ICARO study).

To establish the positive predictive values (PPV) of cfDNA testing based on data from a nationwide survey of independent clinical cytogenetics laboratories. Prenatal diagnostic test results obtained by Italian laboratories between 2013 and March 2020 were compiled for women with positive non-invasive prenatal tests (NIPT), without an NIPT result, and cases where there was sex discordancy between the NIPT and ultrasound. PPV and other summary data were reviewed. Diagnostic test results were collected for 1327 women with a positive NIPT. The highest PPVs were for Trisomy (T) 21 (624/671, 93%) and XYY (26/27, 96.3%), while rare autosomal trisomies (9/47, 19.1%) and recurrent microdeletions (8/55, 14.5%) had the lowest PPVs. PPVs for T21, T18, and T13 were significantly higher when diagnostic confirmation was carried out on chorionic villi (97.5%) compared to amniotic fluid (89.5%) (p<0.001). In 19/139 (13.9%), of no result cases, a cytogenetic abnormality was detected. Follow-up genetic testing provided explanations for 3/6 cases with a fetal sex discordancy between NIPT and ultrasound. NIPT PPVs differ across the conditions screened and the tissues studied in diagnostic testing. This variability, issues associated with fetal sex discordancy, and no results, illustrate the importance of pre- and post-test counselling.

Cytogenetic Analysis of Sporadic First-Trimester Miscarriage Specimens Using Karyotyping and QF-PCR: A Retrospective Romanian Cohort Study.

It is well known that first-trimester miscarriages are associated with chromosome abnormalities, with numerical chromosome abnormalities being the ones most commonly detected. Conventional karyotyping is still considered the gold standard in the analysis of products of conception, despite the extended use of molecular genetic techniques. However, conventional karyotyping is a laborious and time-consuming method, with a limited resolution of 5-10 Mb and hampered by maternal cell contamination and culture failure. The aim of our study was to assess the type and frequency of chromosomal abnormalities detected by conventional karyotyping in specimens of sporadic first-trimester miscarriages in a Romanian cohort, using QF-PCR to exclude maternal cell contamination. Long-term cultures were established and standard protocols were applied for cell harvesting, slide preparation, and GTG banding. All samples with 46,XX karyotype were tested for maternal cell contamination by QF-PCR, comparing multiple microsatellite markers in maternal blood with cell culture and tissue samples. Out of the initial 311 specimens collected from patients with sporadic first-trimester miscarriages, a total of 230 samples were successfully analyzed after the exclusion of 81 specimens based on unsuitable sampling, culture failure, or QF-PCR-proven maternal cell contamination. Chromosome abnormalities were detected in 135 cases (58.7%), with the most common type being single autosomal trisomy (71/135-52.6%), followed by monosomy (monosomy X being the only one detected, 24/135-17.8%), and polyploidy (23/135-17.0%). The subgroup analysis based on maternal age showed a statistically significant higher rate of single trisomy for women aged 35 years or older (40.3%) compared to the young maternal age group (26.1%) (p = 0.029). In conclusion, the combination of conventional karyotyping and QF-PCR can lead to an increased chromosome abnormality detection rate in first-trimester miscarriages. Our study provides reliable information for the genetic counseling of patients with first-trimester miscarriages, and further large-scale studies using different genetic techniques are required.

RNAseq analysis of olfactory neuroepithelium cytological samples in individuals with Down syndrome compared to euploid controls: a pilot study

Down syndrome is a common genetic disorder caused by partial or complete triplication of chromosome 21. This syndrome shows an overall and progressive impairment of olfactory function, detected early in adulthood. The olfactory neuronal cells are located in the nasal olfactory mucosa and represent the first sensory neurons of the olfactory pathway. Herein, we applied the olfactory swabbing procedure to allow a gentle collection of olfactory epithelial cells in seven individuals with Down syndrome and in ten euploid controls. The aim of this research was to investigate the peripheral gene expression pattern in olfactory epithelial cells through RNAseq analysis. Validated tests (Sniffin’ Sticks Extended test) were used to assess olfactory function. Olfactory scores were correlated with RNAseq results and cognitive scores (Vineland II and Leiter scales). All Down syndrome individuals showed both olfactory deficit and intellectual disability. Down syndrome individuals and euploid controls exhibited clear expression differences in genes located in and outside the chromosome 21. In addition, a significant correlation was found between olfactory test scores and gene expression, while a non-significant correlation emerged between olfactory and cognitive scores. This first preliminary step gives new insights into the Down syndrome olfactory system research, starting from the olfactory neuroepithelium, the first cellular step on the olfactory way.Graphical

Epidemiology of aplasia cutis congenita: A population-based study in Europe.

Aplasia cutis congenita (ACC) is a rare congenital anomaly characterized by localized or widespread absence of skin at birth, mainly affecting the scalp. Most information about ACC exists as individual case reports and medium-sized studies. This study aimed to investigate the epidemiology of ACC, using data from a large European network of population-based registries for congenital anomalies (EUROCAT). Twenty-eight EUROCAT population-based registries in 16 European countries were involved. Poisson regression models were exploited to estimate the overall and live birth prevalence, to test time trends in prevalence between four 5-year periods and to evaluate the impact of the change of coding for ACC from the unspecific ICD9-BPA code to the specific ICD10 code. Proportions of ACC cases associated with other anomalies were reported. Five hundred cases were identified in the period 1998-2017 (prevalence: 5.10 per 100,000 births). Prevalence across 5-year periods did not differ significantly and no significant differences were evident due to the change from ICD9 to ICD10 in ACC coding. Heterogeneity in prevalence was observed across registries. The scalp was the most common site for ACC (96.4%) and associated congenital anomalies were present in 33.8% of cases. Patau and Adams-Oliver syndromes were the most frequent among the associated chromosomal anomalies (88.3%) and the associated genetic syndromes (57.7%), respectively. 16% of cases were associated with limb anomalies and 15.4% with congenital heart defects. A family history of ACC was found in 2% of cases. To our knowledge, this is the only population-based study on ACC. The EUROCAT methodologies provide reliable prevalence estimates and proportions of associated anomalies.

Chromosome Aberration on Growth and Developmental Disorder

Growth and development in humans begin at conception, which shows progress and interdependence. Normal children show the characteristic of growth and development. In children with growth and development disorder, chromosomal abnormality may be found. This study aimed to determine chromosomal abnormality in patients with growth and development disorder. The samples were taken from karyotype results of patients in the Medical Genetics Laboratory, Faculty of Medicine, Universitas Wijaya Kusuma Surabaya, from 2010-2020. The inclusion criteria were infants to adolescents aged 24 years and unmarried who experienced impaired growth and development, including sexual development. Chromosomal abnormalities were obtained from cytogenetic analysis using the G-banding method. From 75 samples with growth and development disorders, there were abnormalities in the number of autosomal chromosomes and sex chromosomes found in patients with Down syndrome, Turner syndrome, Klinefelter syndrome, and Edwards syndrome. Chromosomal structural abnormalities found were deletion, translocation, inversion, duplication, marker chromosome, and heteromorphism. This study showed the importance of karyotyping in children and adolescents with growth and developmental disorders.

Cochlear Implantation in a Child with Patau Syndrome.

This study aimed to present the first cochlear implant surgery performed on a patient with Patau syndrome. In the auditory brainstem Response test performed on the 37th month, I-III-V waves at 100 dB were not obtained in the right ear, while I-III-V waves at 90 dB were obtained in the left ear. In the free-field audiometry test done in the first year, the threshold value of cochlear implantation was found to be 45 dB. While the Meaningful Auditory Integration Scale test result was 35/40, the Meaningful Use of Speech Scale test result was 13/40. The cochlear implantation was observed and found that hearing results are good and had a positive effect on the quality of life.

Live-Born Double Aneuploidy at the Johns Hopkins Cytogenomics Laboratory: Case Report and Review of the Literature

Double aneuploidy is the co-occurrence of aneuploidy of two different chromosomes within the same individual. Genomic imbalance associated with two aneuploidies in humans is associated with early lethality, and observation in live-born humans is rare. In isolation, trisomy of chromosomes 13, 18, 21, X, and Y may be better tolerated, whereas monosomy of X is the only such type of aberration that may be compatible with life. It is hypothesized that two successive malsegregation events must occur in early development to be observed constitutionally. Mechanisms like trisomy rescue or selection against aneuploidies may result in mosaicism and promote subsequent survival in live-born individuals, depending on the chromosomes involved. From the literature, double aneuploidy in the live-born is rare, with (acrocentric) autosomal with gonosomal aneuploidy more common than double autosomal aneuploidy. A retrospective case study of patients who underwent routine postnatal cytogenetic testing at The Johns Hopkins Hospital (JHH) Cytogenomics Laboratory (from its inception in the early 1960s-present) was carried out to identify mosaic and/or non-mosaic forms of double aneuploidy. One case each of non-mosaic [Klinefelter with Edwards Syndrome] and non-mosaic [Klinefelter with Down Syndrome] is identified. No gonosomal and autosomal cases in females nor double autosomal trisomies were identified in live-born individuals at the JHH Cytogenomics Laboratory. Given the advancements in non-invasive prenatal screening for common aneuploidies, the need for diagnostic confirmation studies persists. Providers should be aware of the possibility of early detection of pregnancies bearing double aneuploidy (common or rare) when maternal malignancy is not suspected. Additionally, clinicians should consider the possibility of double aneuploidy in rare situations of atypical or blended phenotypes reminiscent of dual diagnoses. Further work is needed to identify and compile these and even rarer double aneuploidy cases to improve genotype-phenotype correlations.

Aβ and tau prions feature in the neuropathogenesis of Down syndrome

Down syndrome (DS) is caused by the triplication of chromosome 21 and is the most common chromosomal disorder in humans. Those individuals with DS who live beyond age 40 y develop a progressive dementia that is similar to Alzheimer's disease (AD). Both DS and AD brains exhibit numerous extracellular amyloid plaques composed of Aβ and intracellular neurofibrillary tangles composed of tau. Since AD is a double-prion disorder, we asked if both Aβ and tau prions feature in DS. Frozen brains from people with DS, familial AD (fAD), sporadic AD (sAD), and age-matched controls were procured from brain biorepositories. We selectively precipitated Aβ and tau prions from DS brain homogenates and measured the number of prions using cellular bioassays. In brain extracts from 28 deceased donors with DS, ranging in age from 19 to 65 y, we found nearly all DS brains had readily measurable levels of Aβ and tau prions. In a cross-sectional analysis of DS donor age at death, we found that the levels of Aβ and tau prions increased with age. In contrast to DS brains, the levels of Aβ and tau prions in the brains of 37 fAD and sAD donors decreased as a function of age at death. Whether DS is an ideal model for assessing the efficacy of putative AD therapeutics remains to be determined.

Excessive negative regulation of type I interferon disrupts viral control in individuals with Down syndrome.

Down syndrome (DS) is typically caused by triplication of chromosome 21. Phenotypically, DS presents with developmental, neurocognitive, and immune features. Epidemiologically, individuals with DS have less frequent viral infection, but when present, these infections lead to more severe disease. The potent antiviral cytokine type I Interferon (IFN-I) receptor subunits IFNAR1 and IFNAR2 are located on chromosome 21. While increased IFNAR1/2 expression initially caused hypersensitivity to IFN-I, it triggered excessive negative feedback. This led to a hypo-response to subsequent IFN-I stimuli and an ensuing viral susceptibility in DS compared to control cells. Upregulation of IFNAR2 expression phenocopied the DS IFN-I dynamics independent of trisomy 21. CD14+ monocytes from individuals with DS exhibited markers of prior IFN-I exposure and had muted responsiveness to exvivo IFN-I stimulation. Our findings unveil oscillations of hyper- and hypo-response to IFN-I in DS, predisposing individuals to both lower incidence of viral disease and increased infection-related morbidity and mortality.

Clinical impacts of genome-wide noninvasive prenatal testing for rare autosomal trisomy

Genome-wide noninvasive prenatal testing identifies several rare autosomal trisomies in the general obstetrical population, but its use is questioned by its low positive predictive value. Furthermore, the origin of rare autosomal trisomies and the clinical effect of reporting them has not been sufficiently investigated. In addition, professional societies express their need for data assessing the clinical use of genome-wide noninvasive prenatal testing for rare autosomal trisomies for years. This study aimed to investigate the origin of rare autosomal trisomies and the clinical effect of disclosing rare autosomal trisomies in clinical settings. Women who received noninvasive prenatal testing between March 2021 and March 2022 were prospectively enrolled. Clinical follow-up and cytogenetic and molecular investigations were performed. Posthoc analysis was performed to investigate the association between placental mosaicism and clinical outcomes. Overall, 154 rare autosomal trisomies were identified in 89,242 pregnancies (0.17%) through noninvasive prenatal testing. In the 120 cases in which cytogenetic and molecular investigations were carried out, the rare autosomal trisomies were found to originate from true fetal mosaicism (n=5), uniparental disomy (n=5), maternal mosaic trisomy (n=3), maternal malignancy (n=1), and confined placental mosaicism (n=106). Clinical follow-up showed that 40% of all rare autosomal trisomy cases had adverse perinatal outcomes. In women with false-positive noninvasive prenatal testing results originating from confined placental mosaicism, the frequency of adverse perinatal outcomes was 26%. More importantly, the placental mosaicism ratio revealed by noninvasive prenatal testing was significantly higher in women who experienced adverse perinatal outcomes than those who did not (0.688 vs 0.332; P<.001). Women with noninvasive prenatal testing results indicative of rare autosomal trisomies are at risk of adverse perinatal outcomes, and that risk can be stratified using chromosomes and the mosaicism ratio revealed by noninvasive prenatal testing. Our data are valuable for obstetrical caregivers advising a patient with a noninvasive prenatal testing result indicative of a rare autosomal trisomy and a false-positive diagnosis and for managing risks during pregnancy.

Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome

With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.

Genome-Wide Cell-Free DNA Test for Fetal Chromosomal Abnormalities and Variants: Unrestricted Versus Restricted Reporting.

This study aimed to compare the screening performance of genome-wide cfDNA testing for chromosomal abnormalities between two periods where additional findings were reported and not reported. Data were obtained from consecutive pregnant women with a singleton pregnancy at ≥10 weeks who requested cfDNA testing during 2015–2019. The performance of screening of the cfDNA test was determined by calculating the concordance rate, detection rate, and false-positive rate. Data from 3981 women were included. The no-result rates were similar between the two reporting periods (2.04% vs. 2.08%). Concordance rates for trisomy 21 and 18 were 100% and 100%, respectively. There were two cases tested high risk for trisomy 13, with a concordance rate of 0%. In total, 12 cases were high risk for any sex chromosome aneuploidy with an overall concordance of 75%, and 15 cases tested high risk for any rare autosomal trisomy, with a 13.3% concordance rate. The detection rates for trisomy 21 and 18 were 100% and 100%, respectively. For any SCA, the detection rate was 90%. For the two reporting periods, the combined false-positive rates were 0.93% and 0.17%, which were significantly different (p = 0.002). Restricting the reporting of additional findings from genome-wide cfDNA analysis has reduced the false-positive rate but without a reduction in the no-result rate.

Chromosomal microarray analysis in pregnancy loss: Is it time for a consensus approach?

To investigate the efficacy and outcomes of chromosomal microarray (CMA) in the cytogenomic evaluation of products of conception (POC). Over a 42-month period, 323 POC samples were tested by CMA. Results were assessed using variables including phenotype, gestational age, results from orthogonal testing, and follow-up parental analysis. CMA identified cytogenetic abnormalities in 47.4% of first trimester losses and 10.9% of second and third trimester losses. Chromosomal microarray results specifically from 5 to 7-week losses showed similar rates of abnormalities (45.6%) compared to those of all first trimester losses combined. CMA and karyotype results were discordant in 20.0% of cases, most likely due to maternal cell overgrowth in culture. The most prevalent abnormalities identified in all losses were autosomal trisomies, followed by triploidy. In 43/323 cases, the observed abnormality suggested a parental aberration that prompted follow-up studies; two of these cases indeed identified an inherited aberration. Our findings of specific types of genetic abnormalities and the respective frequencies by gestational age closely align with those of published karyotype studies, supporting the use of routine CMA testing for POCs. CMA outperforms karyotype analysis because it does not require viable, sterile cultures free of maternal admixture or admixture due to multiple gestations. Finally, CMA results can play an important role in identifying increased recurrence risks for some couples.

Cell-Free Fetal Deoxyribonucleic Acid (cffDNA) Analysis as a Remarkable Method of Non-Invasive Prenatal Screening

The cell-free fetal DNA (cffDNA) analysis for screening fetal genetic anomalies has increased dramatically since its commercialization in 2011 worldwide. In the early weeks of pregnancy, it offers a hassle-free, non-invasive procedure of antenatal screening. It guides and protects mothers from undergoing unwanted risk-laden invasive prenatal testing. cffDNA testing is accurate at detecting the abnormal fetus chromosome among a large pool population. Patau syndrome, Edward syndrome, and Down syndrome are currently being accurately screened by this method. Due to their sensitivity and specificity, they now have become the screening method of choice, approaching almost 100% in various studies with a large sample pool. The latest procedures to analyze cffDNA, like the new digital droplet polymerase chain reaction (ddPCR) and sophisticated next-generation sequencing (NGS), haveincreased detection rates with decreased analyzing time. The latest techniques make it possible to screen large numbers of the population with faster report generation. Screening for Rh incompatibility and its timely prevention is now more accessible and more accurate with the help of cffDNA analysis. The problem arises when we deviate from the primary disease and start testing for anomalies not intended to be screened by cffDNA in the first place. Fetal sex chromosome aneuploidy screening by cffDNA is one area where the test gives mixed results either due to differences in machinery, laboratory parameters, or human error. Other rare occurrences like trisomes, such as trisomy 7, trisomy 16, trisomy 22, and a few microdeletion syndromes are also being screened but with less accuracy. Like every technology, cffDNA analysis is not entirely free of criticism. Its high testing cost, potential to accurately prognosticate the gender of the developing fetus and absence of standard testing practices will become an issue as the test becomes routine worldwide.

Ultrasound findings in prenatal diagnosis of trisomy 18 associated with elevated levels of maternal serum alpha-fetoprotein

Rationale: Trisomy 18, also referred to as Edwards syndrome, is the second most common autosomal trisomy syndrome. Trisomy 18 can be identified during prenatal screening by the detection of abnormal maternal serum results and one or more structural abnormalities on ultrasound. Previous studies confirmed that levels of pregnancy-related plasma protein A, alpha-fetoprotein, and free β-subunit of human chorionic gonadotropin in the serum of pregnant women carrying fetuses with trisomy 18 were lower than those in women with normal pregnancies. Patient concerns: A 29-year-old pregnant woman with a high risk of trisomy 18 underwent maternal serum screening at 16 weeks of gestation. The patient exhibited an elevated level of maternal serum alpha-fetoprotein (125 U/mL; 3.5225-fold higher than the multiple of the median). Ultrasonography revealed multiple abnormalities. Diagnoses: Culture of amniotic fluid cells revealed a karyotype of 47, XY, +18. Interventions and outcomes: The pregnancy was terminated. Lessons: Trisomy 18 can be identified prenatally by detection of abnormal levels of key proteins in the maternal serum, and detection of one or more structural abnormalities by ultrasound screening. Prenatal serological screening combined with ultrasound can effectively diagnose fetuses with trisomy 18 in the second trimester.

THE NATURE OF SEX CHROMOSOME ANEUPLOIDIES IN HUMAN BLASTOCYSTS

Post-implantation studies suggest that certain sex chromosome aneuploidies (SCA) do not result from maternal meiotic non-disjunction and hence may have different characteristics than autosomal trisomies. Our aim was to characterize SCA in the human blastocyst in terms of frequency, relationship with female age, and association with day of development.

Cytogenetic techniques in current biomedical research. PART III: numerical alterations of human karyotype

Numerical abnormalities of karyotype are the result of genome mutations. Unlike gene and chromosomal abnormalities, genome mutations do not disrupt the structure of DNA or chromosomes. The cause of numerical changes in the karyotype is a violation of the mechanism of chromosome segregation during meiosis or mitosis. Like other mutations, genome mutations are a natural mechanism for increasing of genetic diversity in offspring. At the same time, humans usually have negative effects of any numerical deviations from the norm, for this reason, cytogenetic examination of aneuploidies is an important diagnostic tool in medical genetics.A change in the number of sex chromosomes is usually not lethal. The spectrum of detected deviations in the carrier is from inconstant impairment of reproduction but a normal phenotype to malformations of some internal organs, infertility and severe intellectual disabilities. Aneuploidies of autosomes are always a threat to life and health. Only autosomal trisomies on chromosomes 13, 18, 21 and 22 are compatible with live birth, there are solitary reports of the birth of children with polyploidies. At the same time, the prognosis of life is relatively favorable only in the case of trisomy 21, leading to the formation of Down syndrome. Other aneuploidies usually lead to spontaneous termination of pregnancy in the early stages and are discovered in samples of abortion material.In this regard, cytogenetic analysis of chromosomal aneuploidies is used to establish the genetic cause of anomalies and malformations in the postnatal period, delays in speech and psychomotor development, reproduction disorders in adults. Of particular importance is the cytogenetic analysis of the karyotype of embryos in the prenatal period. The proposed lecture analyzes the mechanism of formation of genomic mutations and their diversity. The possible medical consequences of the presence of various types of aneuploidies are considered. To the reader attention is offered syndromes associated with a change in the number of chromosomes in the karyotype. The description is illustrated by real images of patient karyotypes.The lecture is aimed primarily at students of medical and biological specialties, young specialists who plan to use cytogenetic research methods in their practical activities, and doctors who are faced with the need to analyze and interpret the results of cytogenetic analysis. To assimilate the material under discussion, it is recommended to familiarize yourself with the previous lecture of the cycle.

Brain circuit pathology in Down syndrome: from neurons to neural networks.

Down syndrome (DS), a genetic pathology caused by triplication of chromosome 21, is characterized by brain hypotrophy and impairment of cognition starting from infancy. While studies in mouse models of DS have elucidated the major neuroanatomical and neurochemical defects of DS, comparatively fewer investigations have focused on the electrophysiology of the DS brain. Electrical activity is at the basis of brain functioning. Therefore, knowledge of the way in which brain circuits operate in DS is fundamental to understand the causes of behavioral impairment and devise targeted interventions. This review summarizes the state of the art regarding the electrical properties of the DS brain, starting from individual neurons and culminating in signal processing in whole neuronal networks. The reported evidence derives from mouse models of DS and from brain tissues and neurons derived from individuals with DS. EEG data recorded in individuals with DS are also provided as a key tool to understand the impact of brain circuit alterations on global brain activity.