Down Syndrome Cases Research Articles

Microbleeds and Cerebral Amyloid Angiopathy in the Brains of People with Down Syndrome with Alzheimer's Disease.

Cerebrovascular pathology is a significant mediator in Alzheimer's disease (AD) in the general population. In people with Down syndrome (DS), the contribution of vascular pathology to dementia may play a similar role in age of onset and/or the rate of progression of AD. In the current study, we explored the extent of microbleeds (MBs) and the link between cerebral amyloid angiopathy (CAA) and MBs in the frontal cortex (FCTX) and occipital cortex (OCTX) in an autopsy series from individuals with DS (<40 years), DS with AD pathology (DSAD), sporadic AD, and control cases (2-83 years). Sections were immunostained against Aβ1 - 40 and an adjacent section stained using Prussian blue for MBs. MBs were both counted and averaged in each case and CAA was scored based on previously published methods. MBs were more frequent in DS cases relative to controls but present to a similar extent as sporadic AD. This aligned with CAA scores, with more extensive CAA in DS relative to controls in both brain regions. CAA was also more frequent in DSAD cases relative to sporadic AD. We found CAA to be associated with MBs and that MBs increased with age in DS after 30 years of age in the OCTX and after 40 years of age in the FCTX. MB and CAA appear to be a significant contributors to the development of dementia in people with DS and are important targets for future clinical trials.

An autopsy case of Down syndrome associated with low birth weight, congenital heart disease and pulmonary hypertension

An autopsy case of Down syndrome associated with low birth weight, congenital heart disease and pulmonary hypertension

Down syndrome caused by 21; 21 robertsonian translocation

Down syndrome, also known as Trisomy-21, is the most common viable aneuploidy in humans. It was first described as a syndrome by John Langdon Down in 1866 and later Jerome Lejeune and Patricia Jacobs explained the association between the third copy of the 21st chromosome and syndromic manifestations. The usual incidence of Down syndrome is 1 in 700 live births. Of all cases of Down syndrome, 95% are caused by non-disjunction. Robertsonian translocation of 21; 21 is extremely rare. To the best of our knowledge, we are reporting the first case of 21;21 translocation causing Down syndrome from Sri Lanka.

The role of fetal growth restriction in the association between Down syndrome and perinatal mortality

Objective: Down syndrome (DS) is associated with significant risk of perinatal mortality. We hypothesize that this association is primarily mediated through the effects of fetal growth restriction (FGR).Methods: This was a retrospective cohort analysis using the US Natality Database from 2011 to 2013. Analysis was limited to singleton nonanomalous pregnancies or confirmed DS pregnancies without severe structural anomalies between 24 and 42 w in gestation. The risk of stillbirth (SB) associated with DS was estimated using both Cox proportional Hazard (HR) regression and accelerated failure time (AFT) methods. The risk of neonatal mortality was estimated using logistic regression analyses. Mediation analysis was then performed to estimate the effect of small for gestational age (SGA), defined as birthweight ≤10th percentile for gestational age, on perinatal mortality associated with DS. All regression models were selected using backward stepwise elimination method. The final regression models included adjustment for maternal age, hypertension, and diabetes.Results: The final cohort included 2446 DS cases among 9,804,718 births. The overall SB rate was 223.6/1000 births in DS group and 4.7/1000 births without DS (p < .001, adjusted hazard ratio (aHR): 58.25; 95% CI [53.44,63.49]). Based on the AFT model, DS survival-to-delivery rate is 4.3 times lower (TR: 0.23; 95% CI [0.22,0.24]). Thirty-five percentage of the effect of DS on stillbirth was mediated through SGA (% mediation:35.1%; 95% CI [33.7,36.4]). The rate of neonatal mortality among DS was 69.0/1000 births compared with 2.8/1000 births without DS (p < .001, adjusted odds ratio (aOR): 27.16; 95% CI: [22.63,32.60]). Only 11.6% of the effect of DS on neonatal deaths was mediated through SGA (%mediation:11.6%; 95% CI [8.4,10.6]).Conclusion: Over one-third of overall stillbirths were mediated through SGA. Routine surveillance of fetal growth and standard SGA surveillance protocols may reduce the risk of perinatal mortality in DS pregnancies. Conversely, it is important to point out that these surveillance strategies may not be effective two-third of the cases not affected by growth restriction.

Multicentre study “Prenatal diagnosis of Down syndrome in Russia 2005–2015”. II. Ultrasound markers

Objective: to study the effectiveness of the use of ultrasound markers for Down syndrome (DS) in the fetus during ultrasound examinations at 11–14 and 18–21 weeks of gestation based on the results of multicentre analysis in the regions of Russia in 2005–2015 years. Materials. The analysis was based on data from a questionnaire on prenatal diagnosis of DS in 30 regions and cities of Russia in 2015. The data from the questionnaire survey of 12 regions in 2005 and 23 regions in 2010 for analyse the dynamic of prenatal diagnosis of DS in our country was obtained. The questionnaire included the questions about the number of births and pregnant women registered in the region; the total number of cases of DS registered in prenatal and postnatal periods; structures of diagnosed cases of DS depending on the detection period; indications for prenatal karyotype; the number of fetuses with DS and the increase of nuchal translucency in 11–14 weeks of gestation; ultrasound markers of DS in the II trimester of gestation and perinatal outcome in cases of prenatal diagnosis of DS. Results. In the course of the multicentre analysis it was established that the accuracy of identification of DS in the prenatal period in our country was 30,9% in 2005, 38,4% in 2010 and significantly increased to 59,7% in 2015. In 2005, only 17,2% of cases of DS were detected in 11–14 weeks of gestation, in 2010 — 38,2% and increased to 72,1 % (7,6–100%) in 2015. In 24 from 30 regions the proportion of diagnosed cases of trisomy 21 at 11–14 weeks of gestation was 50% or more, and in 11 regions — 90–100%. Increase of nuchal translucency thickness was detected on average in 76,3 % fetuses with DS with a range from 28,1 to 100 %. The most prenatal ultrasound markers in fetuses with DS in the second-trimester were congenital malformations and hypoplasia / absence of nasal bones — 64,9 and 65,5 %, respectively. Further, as the frequency of detection decreased: prenasal thickness (27,6 %), echogenic intracardiac focus (27,1%), pyelectasis (22%), nuchal fold (19,7%), short humerus/femur (17,5%), hyperechogenic bowel (14,6%), ventriculomegaly (11,2%), choroid plexus cysts (7,3%). Conclusion. Ultrasound examination is powerful method for identification the fetuses with DS. Therefore, it is necessary to continue the development of new ultrasound markers of DS for improving its prenatal diagnosis.

Projected number of children with isolated spina bifida or down syndrome in England and Wales by 2020

Children with major congenital anomalies often require lifelong access to health and social care services. Estimating future numbers of affected individuals can aid health and social care planning. This study aimed to estimate the number of children aged 0–15 years living with spina bifida or Down syndrome in England and Wales by 2020. Cases of spina bifida and Down syndrome born during 1998–2013 were identified from the Northern Congenital Abnormality Survey and the National Down Syndrome Cytogenetic Register, respectively. The number of infants born with spina bifida during 1998–2019 were estimated by applying the average prevalence rate in the North of England to actual and projected births in England and Wales. Poisson regression was performed to estimate the number of infants born with Down syndrome in England and Wales during 1998–2013 and 2004–2019. The numbers of children aged 0–15 living with spina bifida or Down syndrome in 2014 and in 2020 were then estimated by multiplying year- and age-specific survival estimates by the number of affected births. An estimated 956 children with isolated spina bifida, 623 children with spina bifida and hydrocephalus and 11,592 children with Down syndrome aged 0–15 years will be living in England and Wales by 2020, increases of 7.2%, 12.0% and 12.7% since 2014, respectively. Due to improvements in survival, an increase in population size and changes in maternal age distribution at delivery, we anticipate further increases in the number of children living with spina bifida or Down syndrome by 2020.

3. Unusual case of mosaic Robertsonian Down syndrome with three cell lines and review of history of Robertsonian translocations at Greenwood Genetic Center

3. Unusual case of mosaic Robertsonian Down syndrome with three cell lines and review of history of Robertsonian translocations at Greenwood Genetic Center

Diagnostic algorithm of Down syndrome by minor physical anomaly.

Background:Down syndrome, most common chromosomal abnormality leading to intellectual disability is being diagnosed by Karyotyping. Due to cost constraints, parents couldn’t afford to do Karyotyping which causes delay in individual and family interventions.Introduction:Down syndrome has characteristic morphological features. The minor physical anomaly (MPA) are insults which occur in utero during embryonic development mostly in first and early second trimester and persists throughout life.Material and Methods:70 karyotyping confirmed cases of Down syndrome (DS), 70 other causes of intellectual disabilities (Other ID) and 70 age matched normal children and adolescents (Average) have been incorporated in the study. The Modified Waldrop's scale (Ismail's 41 item scale) have been applied. Demographic comparison and Decision tree algorithm approach have been analysed by SPSS 25 version.Results and Discussion:The paternal age of childbirth, maternal age of childbirth, maternal age of marriage (P < 0.001), income (P = 0.026) variables are statistically significant in Down's syndrome group in comparison to other two groups whereas age and birth order are not statistically significant. DS group has more MPA (m = 17.04, SD = 5.462), than other ID (m = 5.93, SD = 2.628) and Average group (m = 1.59, SD = 1.378). Big sandal gap, high arched palate and epicanthus are most common three minor anomalies found in Down syndrome. Region wise scoring shows high significance (P < 0.001) in Global head, eyes, ears, mouth, hands and feet in Down syndrome group. The four anomalies; epicanthus, telecanthus, high-arched palate, and curved fifth finger) thus can be grouped as differentiating anomalies. When clinodactyly (item 27) and high arched palate (item 21) are present together or epicanthus (item 08) and telecanthus (item 09) present together sensitivity of diagnosing the case as Down syndrome is 0.945 with negative predictive value 0.979.Conclusion:The simian crease which is being considered as common physical anomaly is not specific for Down syndrome. The large scale study is required to extrapolate the above findings but surely it opens new avenue of research.

Chromosomal Abnormalities in Patients with Intellectual Disability: A 21-Year Retrospective Study

Background: Intellectual disability (ID) has been defined as a considerably reduced ability to understand new or complex information and to learn new skills. It is associated with life-long intellectual and adaptive functioning impairments that have a profound impact on individuals, families, and society. It affects about 3% of the general population. ID often comes out with other mental conditions like attention deficit, hyperactivity, and autism spectrum disorders (ASD), and it can be part of a malformation syndrome that affects other organs. It may be syndromic (S-ID) or non-syndromic (NS-ID). Objective: The aims of this study were to identify the profile of intellectually disable patients being referred for cytogenetic analysis in Morocco, to determine the prevalence of chromosomal abnormalities in a Moroccan group, and to compare the results with those of analogous studies from other countries. Participants: We included data from Moroccan patients with NS-ID and others with S-ID (mostly Down syndrome cases) who have been referred between 1996 and 2016. 1,626 patients were involved in this study, 1,200 were referred with a clinical diagnosis of Down syndrome, 37 were clinically diagnosed for ASD with ID, and 389 were suspected of NS-ID. Results: We identified 1,200 cases of Down syndrome. In 1,096 analyses (91.3%), a cytogenetic variant of trisomy 21 was identified: standard trisomy 21 in 1,037 cases (94.6%), a translocation in 34 cases (3.10%), and mosaicism in 25 cases (2.3%). The cytogenetic analysis among ASD with ID cases did not reveal any specific chromosomal abnormalities. The present study also shows that chromosomal abnormalities were present in 6.43% of the patients with NS-ID (25 abnormal karyotypes out of 389 NS-ID cases). Autosomal structural abnormalities were the largest proportion of chromosomal aberrations. Conclusion: The high rate of chromosomal abnormalities found in the Moroccan patients studied demonstrates the capital importance of cytogenetic evaluation in patients who show ID or any clinical development abnormality.

Down syndrome: a cytogenetic study in North Indian population

Down syndrome constitutes the most common chromosomal abnormality among live births (1 in 730 live births) and most frequent form of intellectual disability. Genetic cause for this syndrome is trisomy of chromosome 21. The cytogenetic profile of Down syndrome includes free trisomy 21, Robertsonian translocations, mosaicism, duplication of the DS critical region and other structural rearrangements involving chromosome 21. Purpose of the study was to confirm the clinical diagnosis of suspected cases of Down syndrome by karyotyping and to evaluate several risk factors associated with trisomy 21 among patients belonging to Lucknow region. Karyotype analysis was done in 46 patients with clinical suspicion of Down syndrome. GTG banding was done according to standard protocols. Findings: out of 46 cases i.e., 43 (93.5%) had abnormal karyogram. All these 43 cases had trisomy 21 (Down's syndrome). Among patients with Down syndrome, free trisomy (n=40; 93%) was most common followed by Robertsonian translocation (n=2; 4.7%) and mosaic trisomy (n=1; 2.3%) respectively. Majority of patients were males (n=27; 62.7%) and there were 16 (37.3%) females. Male to female ratio of Down syndrome patients was 1.68. 50% of patients with Down syndrome were born to mothers falling in age group of 36-40 y. Identification of various types of chromosomal abnormalities in Down syndrome is very important. It aids in management of these children and to aware the affected families about recurrence risk and options available.

Prenatal diagnosis of Down syndrome: A 13-year retrospective study

ObjectiveThe aim of this study is to summarize the experience on prenatal diagnosis of Down syndrome. Materials and methodsThe study includes a retrospective data analysis of 157 prenatally detected cases of Down syndrome, routinely diagnosed among 6448 prenatal investigations performed during a 13-year period (2002–2014) in a single tertiary center. ResultsThe prevalence of diagnosed Down syndrome cases was 2.4%. Maternal age alone was indication for prenatal diagnosis in 47 cases (45.2%), increased first-/second-trimester biochemical screening test in 34 cases (21.7%), abnormal ultrasound examination in 69 cases (43.9%), positive familial history for chromosomal abnormalities in four cases, and high risk for trisomy 21 revealed by cell-free DNA testing in three cases. Ultrasound anomalies were present in total of 94 fetuses (59.8%). The most common abnormality was cystic hygroma found in 46 cases (29.3%). A regular form of Down syndrome (trisomy 21) was found in 147 cases (93.6%), Robertsonian translocation in six cases (3.8%), and mosaic form in four cases (2.6%). ConclusionIn prenatal diagnosis of Down syndrome noninvasive screening methods are important for estimation of individual risks, in both, young population of woman and older mothers, while conventional and molecular cytogenetic methods are essential for definite diagnosis and proper genetic counseling.

Economic analysis of prenatal screening strategies for Down syndrome in singleton pregnancies in Turkey

ObjectivesTo examine the costs and outcomes of different screening strategies for Down Syndrome (DS) in singleton pregnancies. Study designA decision-analytic model was developed to compare the costs and the outcomes of different prenatal screening strategies. Five strategies were compared for women under 35-year of age: 1A) triple test (TT), 2A); combined test (CT), 3A) Non-invasive Prenatal Screening Test by using cell free fetal DNA (NIPT), 4A) and 5A) NIPT as a second-step screening for high-risk patients detected by either TT, or CT respectively. For women ≥35-year of age, 1B) implementing invasive test (amniocentesis –AC) and 2B) NIPT for all women were compared. Data was analyzed to obtain the outcomes, total costs, the cost per women and the incremental cost-effectiveness ratios (ICERs) for screening strategies. ResultsAmong the current strategies for women under 35 years old, CT is clearly dominated to TT, as it is more effective and less costly. Although, the current routine practice (2A) is the least-costly strategy, implementing NIPT as a second step screening to high-risk women identified by CT (5A) would be more effective than 2A; leading to a 10.2% increase in the number of detected DS cases and a 96.3% reduction in procedural related losses (PRL). However, its cost to the Social Security Institution that is a public entity would be 17 times higher and increase screening costs by 1.5 times. Strategy 5A would result in an incremental cost effectiveness of 6,873,082 (PPP) US$ when compared to the current one (2A). Strategy 1B-for offering AC to all women ≥35-year of age is dominated over NIPT (2B), as it would detect more DS cases and would be less costly. On the other hand, there would be 206 PRL associated with AC, but NIPT provides clear clinical benefits as there would be no PRL with NIPT. ConclusionsNIPT leads to very high costs despite its high effectiveness in terms of detecting DS cases and avoiding PRL. The cost of NIPT should be decreased, otherwise, only individuals who can afford to pay from out-of-pocket could benefit. We believe that reliable cost-effective prenatal screening policies are essential in countries with low and smiddle income and high birth rates as well.

Study of congenital heart diseases in patients with Down syndrome in Algeria.

This study aimed to describe and evaluate the type, frequency and patterns of congenital heart diseases (CHDs) in patients with Down Syndrome (DS) in Sétif, Algeria. Down Syndrome, or trisomy 21, is the most common genetic disorder in the world. Data were collected and followed from January 2009 to December 2013. Parental consanguinity documenting pedigree analyzing, chromosome analysis and clinical examination were carried out for all cases. Results have shown that 22 (15.4%; ± 0.06) of the total 143 known cases of DS from DS centres have CHDs and 88 (10.6%; ± 2.2) of the total 770 patients with CHDs collected from public departments at the child and maternity teaching hospital, Sétif, have DS. Among the 110 cases, 75 (68%) have single cardiac abnormalities and 35 (32%) have multiple cardiac abnormalities. The most frequent CHDs were Atrioventricular Septal Defect (AVSD). In conclusion, our study will be helpful to demonstrate the current status of DS and to identify the distribution of CHD in patients with DS in Sétif, Algeria, for further study.

The Prevalence Of Congenital Heart Diseases Among Down's Syndrome Children In Diwaniyah Governorate

Objective :A survey was carried out to assess the prevalence of congenital heart diseases (CHD).Patients And Methods: among (180) Down's syndrome (DS)children in institute for mentally handicapped (Alraga institute) and outpatients referred for ECHO study in Diwaniyah Teaching Hospital.REULTS: It was found that (61.1%) of DS cases studied had CHD with a M:F ratio of 1.5:1. The commonest type of CHD found was ventricular septal defect (VSD), followed by atrial septal defect (ASD), mitral valve prolapse(MVP), tetralogy of fallot (TOF), ,patent ductus arteriosus (PDA) and co-arctation of aorta in (54.5 %, 17.2 %, 14.5 %, 11.8 %, 0.9%, 0.9% respectively). The most common mode of presentation of CHD was recurrent chest infection. It was found that about 17.5% of cases with VSD had spontaneous closure, while only (7.5%) were treated surgically. The rest are left untreated.

THE RELATIONSHIP OF SYNAPTIC PROTEINS WITH AGE IN DOWN SYNDROME

Down's syndrome (DS) is a genetic disorder caused by a triplication of chromosome 21 (chr21); it results in learning disabilities. It is recognised that many people with DS develop Alzheimer neuropathology by the 4thdecade of life. Synapse loss is one of the main pathological findings in the brain of subjects with AD and is an important correlate of cognitive decline, it may be detected by the assessment of key synaptic proteins levels in the post-mortem brain. This study assesses the levels of synaptic proteins in DS cases within the range 10–70 years of age. Post-mortem tissue has been used from a maximum of 90 DS subjects. Three synaptic proteins, β-tubulin, synaptophysin and PSD95, were assessed in the hippocampus, frontal and temporal cortices by western blotting. There was a signifcant decline in β-tubulin in the frontal cortex (Rs= -0.24, n= 86, p= 0.26) and temporal cortex (Rs= -0.37, n= 78, p= 0.001) in respect to age. Synaptophysin also significantly declined with age but only in the temporal cortex (Rs= -0.33, n= 78, p= 0.004). PSD95 did not show a change with age in any region. The present study demonstrates that there a decline in the neuronal marker β-tubulin in frontal and temporal cortices and in synaptophysin in temporal cortex as a function of age. The lack of change in the postsynaptic protein, PSD95, indicates perhaps that presynaptic terminals are more vulnerable than postsynaptic. Further studies will relate concentrations of synaptic proteins to quantitative and qualitative neuropathological markers of Alzheimer's disease.

Pattern of congenital heart diseases among children with Down syndrome attending a tertiary care medical college hospital

Background: Down syndrome (DS) is the most common chromosomal abnormality associated with learning difficulties with reported incidence between1/600 -1/1000 live births. DS (trisomy 21) is the most common chromosomal abnormality seen in clinical practice. Most children with DS have trisomy 21, due to chromosomal non-disjunction during meiosis; however, other abnormalities, such as Robertsonian translocation, mosaic, double or triple aneuploidies have been reported. The association between DS and congenital heart disease (CHD) is well established. Congenital heart disease is the most common cause of death among patients with DS and affected children have an increased risk of mortality.Methods: The present descriptive study was conducted on children who had clinical features suggestive of Down syndrome and who were karyotypically proved as Down syndrome.Results: In 100 cases of down syndrome 60 children were males and 40 children were females. 45 children had congenital heart diseases. The frequency of CHD in down syndrome is 45%. Ventricular septal defect was the most common CHD found 40% children with down syndrome.Conclusions: All children with Down’s syndrome should have a cardiac evaluation at birth. Early referral and screening of all babies born with the clinical phenotype of DS should be encouraged due to the high prevalence of congenital heart defects.

The recurrence of sonographic 'soft markers': ominous sign or 'just' genetics?

'Soft markers' (SMs) are nonspecific findings that might convey a higher risk for Down syndrome. We sought to determine the recurrence rate of the most common SM in subsequent pregnancies. This is a retrospective study of all women who underwent early or late fetal sonographic anatomical screening in our ultrasound unit. The examined SMs were pyelectasis, thickened nuchal fold (TNF) and echogenic intracardiac foci (EIF). Data on recurrence and pregnancy outcome were retrieved retrospectively. The database included 20672 singleton pregnancies; SMs were detected in 2347 (11.1%) of the fetuses and were isolated in 1739 (74%). Rates of solitary findings in the pregnancies were 6.5% (1360/20672) EIF, 3% (624/18850) TNF and 1.7% (363/20672) pyelectasis. The recurrence rate of EIF, TNF and pyelectasis in subsequent consecutive pregnancies was 21%, 27% and 16%, respectively. Overall, 62 cases of Down syndrome were diagnosed in (1:333 pregnancies). No cases were diagnosed in patients with recurrent SMs. The high recurrence rate of solitary SM implies for genetic predisposition. These results might improve our counseling for pregnant women affected by the reappearance of solitary SM. Further studies are needed to assess the likelihood ratio for SM if recurrence occurs. © 2017 John Wiley & Sons, Ltd.

Descripción de un caso de bradiarritmia en pacientes con síndrome de Down sin enfermedad cardiaca congénita

Introducción. Los pacientes con síndrome de Down sin enfermedad cardiaca estructural pueden presentar disfunción de la regulación autonómica cardiaca, lo cual se manifiesta mediante una contestación reducida de la frecuencia cardiaca (FC) frente a los estímulos. Con base en las respuestas hemodinámicas, se postuló que dichos pacientes tienen una reducción en las retirada vagales y la activación simpática. En esta revisión se explica el rol del sistema autonómico en el control de la FC y la respuesta cronotrópica atenuada observada en esta población.Objetivo. Describir, mediante la presentación de un caso clínico, la disfunción autonómica presente en los pacientes con síndrome de Down a fin de identificar las causas atribuidas por la evidencia científicaMateriales y métodos.Se describió un caso clínico y se realizó una búsqueda a través de PubMed con los términos: “Down Syndrome” AND “Bradycardia”, “VO2peak”, “Heart Rate Variability”, “Vagal Withdrawal”, “Sympathetic Activation”.Resultados. Los hallazgos sugieren que el ejercicio físico puede ser una intervención efectiva para mejorar la función cardiaca autonómica en personas con síndrome de Down. Además, las mejoras inducidas por el entrenamiento fueron alcanzadas por los participantes con niveles más bajos de modulación vagal al inicio del estudio en pacientes con y sin discapacidad, por lo que el entrenamiento puede ser eficaz para mejorar la aptitud cardiorespiratoria en quienes tienen un mayor grado de disfunción autonómica.Conclusión. Se presentó un caso clínico de síndrome de Down con disfunción sinusal, que podía estar relacionado con la disfunción de la regulación de la función cardiaca autonómica, dada por una FC reducida frente a los estímulos.

Proteotyping Gene Dosage Effects in Genetic Diseases

Introduction and ObjectivesGene dosage imbalance is a general working hypothesis for studying the genetic diseases, such as human syndromes, because the DNA copy number variations (CNVs) are causal for many genetic diseases. However, recent important studies have showed that many CNVs resulting in mRNA changes only weakly influence corresponding protein abundances. Herein we show by proteome‐wide turnover analysis that CNV's substantially remodel the proteome. In the presentation we will discuss specific instances of CNV's varying in the extent and magnitude of affected loci, and disease phenotypes. These examples include trisomy 21 (T21) in human Down Syndrome, and Williams Syndrome (WBS) and 7dup‐ASD syndrome caused by 7q11.23 hemideletion or hemiduplication.MethodsWe utilized SWATH mass spectrometry (SWATH‐MS) to accurately quantify protein degradation through a pulse SILAC experiment (pSILAC) up to 24 hours. For T21, we used fetal skin fibroblasts derived from a pair of monozygotic twins discordant for T21. To validate the results, we also analyzed fibroblasts from 11 unrelated T21 individuals bearing Down Syndrome and 11 controls. For WBS, patient‐derived induced pluripotent stem cells were analyzed. Data were processed by OpenSWATH workflow. The transcript profiling was measured by RNA‐Seq.Results and DiscussionIn the case of Down Syndrome, we investigated the effect of T21 at the levels of transcript quantity, proteome quantity and protein turnover rate. We quantified 4056 unique proteins for expression and ~2200 proteins by pSILAC experiment for turnover analysis in both normal and T21 twins. The T21/normal fold‐change correlation between transcript and protein levels was extremely low, indicating substantial post‐transcriptional regulation and buffering effects in T21. Overall, the protein degradation was faster in trisomy cells than the controls. Remarkably, those Chr21 encoded proteins that are members of heteromeric protein complexes were largely exempt from responding to CNV alterations, primarily through accelerated protein degradation. Moreover, we found that both mitochondrial and cytosolic ribosomal proteomes were degraded heavily in T21, but different degree of translational regulation shaped their final, divergent expression levels. In the case of WBS, we found that proteins with significant differences in turnover at the pluripotent state are components of pathways involved in translation, ubiquitination, splicing and basal metabolism.ConclusionsOur data suggests that protein‐specific turnover presents a primary mechanism of proteome remodeling in response to DNA dosage alterations and thus highlighting a proteomic understanding of “gene dosage imbalance” in genetic disorders.Support or Funding InformationY.L. was supported by the European Research Council (ERC, consolidator grant number 616441‐DISEASEAVATARS). The group of RA was supported by was supported by ERC grants Proteomics v3.0 (AdG‐233226 Proteomics v.3.0) and AdG‐670821 Proteomics 4D), and the Swiss National Science Foundation (SNSF) grant number: 31003A_166435.

Antenatal prognostic factor of fetal echogenic bowel

ObjectiveThe aim of this study was to identify antenatal prognostic factors of neonatal outcomes in cases of fetal echogenic bowel (FEB). Study designA retrospective study in three tertiary referral centers including fetal echogenic bowel over a 10-year period (from January 2003 to December 2013). The echogenicity of the fetal bowel was graded from 1 to 3, according to Slotnick's definition. Associated echographic findings such as bowel dilations, gallbladder abnormalities, calcifications, extra-abdominal abnormalities, intrauterine growth restriction (IUGR) and a decrease in amniotic fluid volume, if present were also recorded. This was followed by the FEB's sonographic evolution. The sonographic evolution was considered favorable if it was stable or decreasing and unfavorable if the echogenicity of the bowel increased or if additional sonographic findings appeared. Neonates had a pediatric examination in the delivery room and upon discharge from the maternity hospital. An outcome was considered good in the case of on-term delivery of a newborn with normal clinical examination and meconium elimination. ResultsComplete pregnancy outcome data were available for 409 pregnancies. 338 newborns had uneventful outcomes (82.6%). Antenatal exploration diagnosed 4 cases of aneuploidy (1 case of trisomy 13, 1 case of trisomy 18 and 2 cases of triploidies), 16 cases of congenital infections, 9 cases of cystic fibrosis and 11 cases of bowel abnormalities. After a multivariate analysis, we discovered the sonographic grade of the echogenic bowel was not a prognostic factor of neonatal outcome. The isolated fetal echogenic bowel had a 6.6-fold increase chance of uneventful outcomes (adjusted odd ratio (aOR) 6.6, 95% CI 3–14.4). Notably, favorable sonographic evolution (aOR 8.1, 95% CI 4.1–16) and late gestational age at the time of the diagnosis (aOR 1.17, 95% CI 1.07–1.27) are independent, good prognostic factors of good neonatal outcomes. None of the 180 fetuses with isolated fetal echogenic bowel and favorable sonographic evolution had adverse outcomes. Among these, 4 cases (0.98%) of aneuploïdy, 17 cases (4.2%) of congenital infections and 9 cases (2.2%) of cystic fibroses were also diagnosed. No cases of Down syndrome (DS) were reported. ConclusionOur study shows that the grade should not be considered a prognostic factor of neonatal outcomes. Our data suggests the need to reevaluate the concept of systematic amniocentesis. Sonographic evolution of fetal bowel is an independent, strong prognostic factor for good neonatal outcomes. It also better defines the FEB prognostic.