Assessing autosomal aneuploidy in ancient genomes.

Using genetic methods, aneuploidies can be detected in ancient human remains, which is so far the only way to reliably prove their existence in the past. As highlighted in recent studies by Rohrlach et al. and by Anastasiadou et al., this initial step enables a deeper exploration of the history of rare diseases, encompassing the social and historical contexts of the afflicted individuals.

Cognitive and functional performance and plasma biomarkers of early Alzheimer's disease in Down syndrome.

INTRODUCTION: People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials. METHODS: This large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aß)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years). RESULTS: In general linear models lower plasma Aß42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory. DISCUSSION: Plasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest. Highlights: Plasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.

Rapidly Progressive Contralateral Internal Carotid Artery Stenosis After COVID-19 Infection in a Down Syndrome Patient With Unilateral Moyamoya Arteriopathy.

Moyamoya arteriopathy is a condition where chronic, progressive stenosis of large intracranial arteries, primarily of the anterior circulation, results in ischemia and the growth of small, abnormal collateral vessels. There is increasing evidence that infectious pathologies, such as COVID-19, may serve as a sort of trigger, or "second hit," for the development of moyamoya arteriopathy. In this article, we present the case of a 13-year-old female with Down syndrome and unilateral moyamoya arteriopathy who developed contralateral internal carotid artery (ICA) dissection and thrombus in the setting of a positive COVID-19 test and subsequently developed rapidly progressive contralateral ICA and bilateral anterior cerebral artery (ACA) moyamoya-like stenosis. The rapidly progressive contralateral ICA and bilateral ACA moyamoya-like stenosis are likely multifactorial in nature. The contralateral ICA may have had a predisposition for injury and stenosis due to the preexisting moyamoya arteriopathy, making stenosis more likely after COVID-19-induced vascular inflammation and injury as well as after a possible thrombectomy-associated injury. Based on this presentation, patients with moyamoya arteriopathy may be at risk for rapid progression of their moyamoya pathology when exposed to catalysts, including infection, such as COVID-19, and vascular injury, such as thrombectomy-induced injury. In these circumstances, high suspicion and close monitoring are essential for addressing ischemia related to the stenosis before permanent injury.

Laryngotracheomalacia in a Patient with Mosaic Trisomy 8.

Mosaic trisomy 8 is a condition characterized by a great phenotypic and cytogenetic variability whose incidence ranges around 1 in 25,000 to 50,000 live births. Here, we report a mosaic trisomy 8 patient presenting laryngotracheomalacia, an uncommon finding, analyzing its possible role over morbidity, and mortality. The patient was a boy who, after birth, had tachypnea and paleness. He presented periods of respiratory dysfunction with need of ventilatory support. Respiratory syncytial virus test was positive. Naso fibrobronchoscopy showed moderate laryngotracheomalacia. He also had recurrent episodes of pneumonia and difficulty in withdrawing continuous positive airway pressure. The patient also presented leucoma, abnormal and low-set ears, pectus excavatum, clenched fists with overlapping fingers, cryptorchidism, clubfeet, and deep longitudinal plantar creases. G-bands by Trypsin using giemsa (GTG-banding) karyotype from a peripheral blood sample revealed a mosaic trisomy 8: mos 47,XY, + 8[15]/46,XY[7]. At 4 months, the patient developed respiratory failure, and a chest computed tomography scan showed areas of atelectasis and gross fibroatelectatic striae. He ended up presenting clinical worsening and died at 4 months and 8 days. In our literature review, we found some reports describing patients with mosaic trisomy 8 and laryngotracheomalacia. However, we cannot rule out the possibility that this association could be casual, since laryngotracheomalacia is a relatively common finding in children. Therefore, more studies are still necessary to understand the possible relation between both conditions and the role of laryngotracheomalacia over morbidity and prognosis of mosaic trisomy 8 patients.

Clinical manifestations and the prenatal diagnosis of trisomy 7 mosaicism: Two case reports.

BACKGROUND: The clinical manifestations of trisomy 7 mosaicism are diverse and nonspecific, so prenatal diagnosis is very difficult. CASE SUMMARY: Two pregnant women with abnormal prenatal screening results were included. One was a 22-year-old woman (G1P0). At 31st week of gestation, ultrasound revealed that the posterior horn of the left lateral ventricle was 10 mm and the right renal pelvis had a separation of 7 mm. The other pregnant woman was 33 years old (G2P1L1A0), and her fetus was found to have a cardiac malformation at the 24th week of gestation. Copy number variation sequencing, whole-exome sequencing and karyotype analysis were carried out after amniocentesis, and both fetuses were diagnosed with trisomy 7 mosaicism. After parental counseling, one woman continued the pregnancy, and the other woman terminated the pregnancy. CONCLUSION: In trisomy 7 mosaicism, the low proportion of trisomy does not lead to abortion, but can result in abnormal fetal development, which can be detected via ultrasound. Therefore, clinicians need to pay more attention to various aspects of fetal growth and development, combining with imaging, cellular, molecular genetics and other methods to perform comprehensive evaluations of fetuses to provide more reliable genetic counseling for pregnant women.

Prenatal diagnosis of 18p deletion and 8p trisomy syndrome: literature review and report of a novel case.

18p deletion syndrome constitutes one of the most frequent autosomal terminal deletion syndromes, affecting one in 50,000 live births. The syndrome has un-specific clinical features which vary significantly between patients and may overlap with other genetic conditions. Its prenatal description is extremely rare as the fetal phenotype is often not present during pregnancy. Trisomy 8p Syndrome is characterized by heterogenous phenotype, with the most frequent components to be cardiac malformation, developmental and intellectual delay. Its prenatal diagnosis is very rare due to the unspecific sonographic features of the affected fetuses. We present a very rare case of a fetus with multiple anomalies diagnosed during the second trimester whose genomic analysis revealed a 18p Deletion and 8p trisomy Syndrome. This is the first case where this combination of DNA mutations has been described prenatally and the second case in general. The presentation of this case, as well as the detailed review of all described cases, aim to expand the existing knowledge regarding this rare condition facilitating its diagnosis in the future.

Clinical outcomes of screen-positive genome-wide cfDNA cases for trisomy 20: results from the global expanded NIPT Consortium.

Trisomy 20 has been shown to be one of the most frequent rare autosomal trisomies in patients that undergo genome-wide noninvasive prenatal testing. Here, we describe the clinical outcomes of cases that screened positive for trisomy 20 following prenatal genome-wide cell-free (cf.) DNA screening. These cases are part of a larger cohort of previously published cases. Members of the Global Expanded NIPT Consortium were invited to submit details on their cases with a single rare autosomal aneuploidy following genome-wide cfDNA screening for retrospective analysis. Clinical details including patient demographics, test indications, diagnostic testing, and obstetric pregnancy outcomes were collected. Genome-wide cfDNA screening was conducted following site-specific laboratory procedures. Cases which screened positive for trisomy 20 (n = 10) were reviewed. Clinical outcome information was available for 90% (9/10) of our screen-positive trisomy 20 cases; the case without diagnostic testing ended in a fetal demise. Of the nine cases with outcome information, one was found to have a mosaic partial duplication (duplication at 20p13), rather than a full trisomy 20. Only one case in the study cohort had placental testing; therefore, confined placental mosaicism could not be ruled out in most cases. Adverse pregnancy outcomes were seen in half of the cases, which could suggest the presence of underlying confined placental mosaicism or mosaic/full fetal trisomy 20. Based on our limited series, the likelihood of true fetal aneuploidy is low but pregnancies may be at increased risk for adverse obstetric outcomes and may benefit from additional surveillance.

Optimal Treatment Approaches to Intestinal Behçet's Disease Complicated by Myelodysplastic Syndrome: The KASID and KSBD Multicenter Study.

PURPOSE: Studies on intestinal Behçet's disease (BD) complicated by myelodysplastic syndrome (MDS) are rare, and no established therapeutic guidelines exist. This study aimed to evaluate the clinical presentation and outcomes of patients with intestinal BD complicated by MDS (intestinal BD-MDS) and suggest a treatment strategy. MATERIALS AND METHODS: Data from patients with intestinal BD-MDS from four referral centers in Korea who were diagnosed between December 2000 and December 2022 were retrospectively analyzed. Clinical features and prognosis of intestinal BD-MDS compared with age-, sex-matched intestinal BD without MDS were investigated. RESULTS: Thirty-five patients with intestinal BD-MDS were included, and 24 (70.6%) had trisomy 8. Among the 35 patients, 23 (65.7%) were female, and the median age at diagnosis for intestinal BD was 46.0 years (range, 37.0-56.0 years). Medical treatments only benefited eight of the 32 patients, and half of the patients underwent surgery due to complications. Compared to 70 matched patients with intestinal BD alone, patients with intestinal BD-MDS underwent surgery more frequently (51.4% vs. 24.3%; p=0.010), showed a poorer response to medical and/or surgical treatment (75.0% vs. 11.4%; p<0.001), and had a higher mortality (28.6% vs. 0%; p<0.001). Seven out of 35 patients with intestinal BD-MDS underwent hematopoietic stem cell transplantation (HSCT), and four out of the seven patients had a poor response to medical treatment prior to HSCT, resulting in complete remission of both diseases. CONCLUSION: Patients with intestinal BD-MDS frequently have refractory diseases with high mortalities. HSCT can be an effective treatment modality for medically refractory patients with intestinal BD-MDS.

Parents of children with Down syndrome reflect on their postnatal diagnoses, 2003-2022.

A 2003 survey revealed the scope of mothers' dissatisfaction with their postnatal support following a diagnosis of Down syndrome (DS). Substantial proportions of mothers reported that providers conveyed diagnoses with pity, emphasized negative aspects of DS, and neglected to provide adequate materials explaining DS. This study follows up on the 2003 survey by assessing whether parents' experiences have improved. Four DS nonprofit organizations, which participated in the original study, distributed a mixed-methods survey to families who have had children with DS between 2003 and 2022. Quantitative analysis assessed correlations among responses and differences between the 2003 and 2022 survey groups. Open-ended responses were qualitatively analyzed. Compared to the 2003 findings, parents' perceptions of their postnatal care have not improved (N = 89). Parents are increasingly likely to report that their providers pitied them, omitted positive aspects of DS, and provided insufficient materials describing DS. Substantial proportions of parents reported fear (77%) and anxiety (79%), only 24% described receiving adequate explanatory materials, and parents were 45% likelier to report that physicians discussed negative aspects of DS than positive aspects. Qualitatively, substantial numbers of parents recounted insensitive conduct by providers. These results suggest that despite interventions, parents' experiences of postnatal diagnoses of DS have not improved over time. Certain provider behaviors-such as describing positive aspects of DS and providing comprehensive explanatory materials-can reduce fear and anxiety, pointing to directions for reform.

Intussusception in Mosaic Trisomy 14.

Mosaic trisomy 14 is exceptionally rare and was first described in the 1970s with fewer than 100 known liveborn individuals. Information about complications and the natural history of the disease is rare, especially in adult patients. This case illustrates an adult patient with severe functional limitations from mosaic trisomy 14 who presented with abdominal pain and failure to thrive and was subsequently found to have intussusception and severe chronic constipation, which was successfully treated conservatively.

A maternally derived complex small supernumerary marker chromosome involving chromosomes 8 and 14: case report and review of the literature.

Introduction: The majority of small supernumerary marker chromosomes (sSMCs) are derived from one single chromosome. Complex sSMCs, on the other hand, consist of genetic material derived from more than one, normally two chromosomes. Complex sSMCs involving chromosomes 8 and 14 are rarely encountered. Case presentation: We present here a 14-month-old boy born from an unrelated couple. At birth, the baby was hypotonic and had a cleft lip and palate, as well as ocular involvement. Throughout the course of development, the baby experienced feeding difficulties, stunted growth, and delayed psychomotor development. Banding together with molecular cytogenetics revealed a balanced maternal translocation t(8;14)(p22.3;q21)mat, leading due to meiotic 3:1 segregation to a partial trisomy of chromosomes 8 and 14 in the affected boy. Discussion/Conclusion: This report highlights the importance of cytogenetics in diagnosis of rare genetic disorders, with impact on genetic counselling of patients and their families. There are three comparable cases in the literature involving both chromosomes 8 and 14, but with different breakpoints; the complex sSMC derived from chromosomes 8 and 14 in this case, characterized as der(14)t(8;14) (p22.3;q21)mat.

Trisomy 22 Mosaicism from Prenatal to Postnatal Findings: A Case Series and Systematic Review of the Literature.

BACKGROUND: Among aneuploidies compatible with life, trisomy 22 mosaicism is extremely rare, and only about 25 postnatal and 18 prenatal cases have been described in the literature so far. The condition is mainly characterized by facial and body asymmetry, cardiac heart defects, facial dysmorphisms, growth failure, delayed puberty, and variable degrees of neurodevelopmental delay. PROBLEM: The scattered information regarding the condition and the dearth of data on its natural history and developmental outcomes restrict genetic counseling, particularly in prenatal settings. Moreover, a prompt diagnosis is frequently delayed by the negative selection of trisomic cells in blood, with mosaicism percentage varying among tissues, which often entails the need for further testing. Purpose/topic: The aim of our work is to provide assistance in prenatal and postnatal genetic counseling by systematically delineating the current knowledge of the condition. This entails defining the prenatal and postnatal characteristics of the condition and presenting novel data from three cases, both prenatally and postnatally. Additionally, we report the developmental outcomes observed in two new patients.

Prevalence of sex-chromosome aneuploidy estimated using SNP genotype intensity information in a large population of juvenile dairy and beef cattle.

Aneuploidy is a genetic condition characterized by the loss or gain of one or more chromosomes. Aneuploidy affecting the sex chromosomes can lead to infertility in otherwise externally phenotypically normal cattle. Early identification of cattle with sex chromosomal aneuploidy is important to minimize the costs associated with rearing infertile cattle and futile breeding attempts. As most livestock breeding programs routinely genotype their breeding populations using single nucleotide polymorphism (SNP) arrays, this study aimed to assess the feasibility of integrating an aneuploidy screening tool into the existing pipelines that handle dense SNP genotype data. A further objective was to estimate the prevalence of sex chromosome aneuploidy in a population of 146,431 juvenile cattle using available genotype intensity data. Three genotype intensity statistics were used: the LogR Ratio (LRR), R-value (the sum of X and Y SNP probe intensities), and B-allele frequency (BAF) measurements. Within the female-verified population of 124,958 individuals, the estimated prevalence rate was 0.0048% for XO, 0.0350% for XXX, and 0.0004% for XXY. The prevalence of XXY in the male-verified population was 0.0870% (i.e., 18 out of 20,670 males). Cytogenetic testing was used to verify 2 of the XXX females who were still alive. The proposed approach can be readily integrated into existing genomic pipelines, serving as an efficient, large-scale screening tool for aneuploidy. Its implementation could enable the early identification of infertile animals with sex-chromosome aneuploidy.

Transcranial Direct Current Stimulation in neurogenetic syndromes: new treatment perspectives for Down syndrome?

This perspective review aims to explore the potential neurobiological mechanisms involved in the application of transcranial Direct Current Stimulation (tDCS) for Down syndrome (DS), the leading cause of genetically-based intellectual disability. The neural mechanisms underlying tDCS interventions in genetic disorders, typically characterized by cognitive deficits, are grounded in the concept of brain plasticity. We initially present the neurobiological and functional effects elicited by tDCS applications in enhancing neuroplasticity and in regulating the excitatory/inhibitory balance, both associated with cognitive improvement in the general population. The review begins with evidence on tDCS applications in five neurogenetic disorders, including Rett, Prader-Willi, Phelan-McDermid, and Neurofibromatosis 1 syndromes, as well as DS. Available evidence supports tDCS as a potential intervention tool and underscores the importance of advancing neurobiological research into the mechanisms of tDCS action in these conditions. We then discuss the potential of tDCS as a promising non-invasive strategy to mitigate deficits in plasticity and promote fine-tuning of the excitatory/inhibitory balance in DS, exploring implications for cognitive treatment perspectives in this population.

A case report of Pallister-Killian syndrome with an unusual mosaic supernumerary marker chromosome 12 with interstitial 12p13.1-p12.1 duplication.

Pallister-Killian syndrome (PKS) is a rare inherited disease with multiple congenital anomalies, profound intellectual disability, and the presence in the karyotype of sSMC - i(12)(p10). The frequency of PKS may be underestimated due to problems with cytogenetic diagnosis caused by tissue-specific mosaicism and usually a low percentage of peripheral blood cells containing sSMC. Such tissue-specific mosaicism also complicates a detailed analysis of the sSMC, which, along with the assessment of mosaicism in different tissues, is an important part of cytogenetic diagnosis in PKS. Unfortunately, a full-fledged diagnosis in PKS is either practically impossible or complicated. On the one hand, this is due to problems with the biopsy of various tissues (skin biopsy with fibroblast culture is most often used in practice); on the other - a low percentage of dividing peripheral blood cells containing sSMC, which often significantly complicates the analysis of its composition and organization. In the present study, a detailed analysis of sSMC was carried out in a patient with a characteristic clinical picture of PKS. A relatively high percentage of peripheral blood cells with sSMC (50%) made it possible to perform a detailed molecular cytogenetic analysis of de novo sSMC using chromosomal in situ suppression hybridization (CISS-hybridization), multicolor FISH (mFISH), multicolor chromosome banding (MCB), array CGH (aCGH), and quantitative real-time PCR (qPCR), and short tandem repeat (STR) - analysis. As a result, it was found that the sSMC is not a typical PKS derivative of chromosome 12. In contrast to the classical i(12)(p10) for PKS, the patient's cells contained an acrocentric chromosome consisting of 12p material. Clusters of telomeric repeats were found at the both ends of the sSMC. Furthemore, the results of aCGH and qPCR indicate the presence of interstitial 8.9 Mb duplication at 12p13.1-p12.1 within the sSMC, which leads to different representations of DNA from different segments of 12p within cells containing sSMC. The obtained data raise the question of the instability of the sSMC and, as a consequence, the possible presence of additional rearrangements, which, in traditional cytogenetic analysis of patients with PKS, are usually described as i(12)(p10).

Results of inaugural international Down Syndrome Societal Services and Supports survey.

PURPOSE: We previously designed the Down Syndrome Societal Services and Supports Survey (DS-4S) to measure country-specific supports for people with Down syndrome (DS) across multiple life domains (healthcare, education, policy, independence, and community inclusion). We now report and analyze the results. METHODS: We partnered with international DS consortia, who distributed the DS-4S to 154 cumulative members representing over 100 countries. Organizations were included if they had a holistic focus on the lives of people with DS and if at least 50% of their members either have DS or are family members of people with DS. Factor analysis was used to analyze the results. RESULTS: We received survey responses from 55 different organizations in 50 countries who met inclusion criteria. Each country had complete data for at least 4 of the 5 domains. The lowest 5 scores were from countries in Africa and Asia; the highest 5 scores were in Europe and North America. CONCLUSION: The responses to the DS-4S stratified countries within each surveyed domain. The DS-4S can now be used to track countries' progress over time and to determine which countries have best practices that might be replicated. We will publish the results and update them biennially at www.DownSyndromeQualityOfLife.com.

Chromosomal abnormalities associated with fetal pleural effusion (II): Specific and non-specific chromosome aberrations.

Fetal pleural effusion has been reported to be associated with chromosomal abnormalities, genetic syndromes, obstructive uropathy, lymphatic vessel abnormalities such as Noonan syndrome, RASopathy and congenital lymphatic anomalies, thoracic cavity defects, Rh or ABO incompatibility, non-immune hydrops fetalis, infections, congenital cardiac anomalies, metabolic diseases and hematologic diseases such as α-thalassemia. This review provides a comprehensive view of specific and non-specific chromosome aberrations associated with fetal pleural effusion which is useful for genetic counseling and fetal therapy at prenatal diagnosis of fetal pleural effusion.

Alzheimer's drugs, APPlication for Down syndrome?

Accumulation of the amyloid ß (Aß) peptide, derived from Aß precursor protein (APP), is a trait of Down syndrome (DS), as is early development of dementia that resembles Alzheimer's disease (AD). Treatments for this AD in DS simply do not. New drug therapies for AD, e.g., Lecanemab, are monoclonal antibodies designed to clear amyloid plaques composed of Aß. The increasingly real ability to target and dispose of Aß favors the use of these drugs in individuals with AD in DS, and, perhaps as earlier intervention for cognitive impairment. We present pertinent similarities between DS and AD in adult DS subjects, discuss challenges to target APP metabolites, and suggest that recently developed antibody treatments against Aß may be worth investigating to treat AD in DS.

"She was finally mine": the moral experience of families in the context of trisomy 13 and 18- a scoping review with thematic analysis.

INTRODUCTION: The value of a short life characterized by disability has been hotly debated in the literature on fetal and neonatal outcomes. METHODS: We conducted a scoping review to summarize the available empirical literature on the experiences of families in the context of trisomy 13 and 18 (T13/18) with subsequent thematic analysis of the 17 included articles. FINDINGS: Themes constructed include (1) Pride as Resistance, (2) Negotiating Normalcy and (3) The Significance of Time. INTERPRETATION: Our thematic analysis was guided by the moral experience framework conceived by Hunt and Carnevale (2011) in association with the VOICE (Views On Interdisciplinary Childhood Ethics) collaborative research group. RELEVANCE: This article will be of interest and value to healthcare professionals and bioethicists who support families navigating the medically and ethically complex landscape of T13/18.

Trisomy 13 with retroiliac ureter diagnosed by assessment for recurrent febrile urinary tract infections.

Introduction: Patients with trisomy 13 have multiple malformations, including urological anomalies, and severe cognitive and psychomotor disabilities. We conducted a ureteroureterostomy for a mid-ureteral stricture due to a retroiliac ureter in a patient with trisomy 13. Case presentation: A 6-month-old girl with trisomy 13 developed a urinary tract infection. Computed tomography for assessing recurrent urinary tract infection revealed a left mid-ureteral stricture due to the retroiliac ureter. At the age of 2, a ureteroureterostomy was performed. Two years after surgery, the urinary tract infection did not recur. Conclusion: Ureteroureterostomy is a safe procedure for children with trisomy 13 and multiple comorbidities. Surgical treatment should be considered for patients with trisomy 13 when agreed upon by the family and comorbidities are well-controlled.