Risk For DS Research Articles

Generation of microglia‐containing APOE4 cerebral organoids as a model of Down syndrome associated Alzheimer’s disease

AbstractBackgroundDown syndrome (DS) is among the most common forms of familial Alzheimer’s disease (AD), resulting from triplication of the amyloid precursor protein (APP) gene on chromosome 21 which leads to increased amyloid beta (Aβ) peptide accumulation in the brain. As a result, all people with DS will develop Aβ plaques and tau tangles by the age of 40, and the majority will eventually develop AD‐related cognitive decline. Carrying the e4 allele of the apolipoprotein E gene (APOE), APOE4, because it catalyzes the formation of neurotoxic Aβ oligimers. The combination of APOE4 and trisomy 21 results in a very high risk for DS associated AD. APOE4 has also been shown to drive altered microglial activity in the AD brain, leading to increased neuroinflammation, neurodegeneration and cognitive decline. Studying mechanisms underlying APOE4‐microglial interactions could lead to identification of new therapeutic targets for DS‐AD treatments. Microglia‐containing cerebral organoids (MCOs) derived from human induced pluripotent stem cells (hiPSCs) with both trisomy 21 and APOE4 would offer a distinct advantage over prior models.MethodIsogenic hiPSC disomic or trisomic for chromosome 21 from an individual mosaic for trisomy 21 and carrying the APOE3/3 genotype and CRISPR‐Cas9 gene editing was then used to generate hiPSCs with the APOE4/4 genotype. hiPSCs were then differentiated into hematopoetic progenitor cells (HPCs) and neural progenitor cells (NPCs) and co‐cultured at a 7:3 ratio (NPCs:HPCs) to form MCOs.ResultControl cerebral organoids (COs) lacking HPCs were reduced in size compared to age‐matched MCOs, suggesting the successful integration of HPCs with NPCs during co‐culture. Immunohistochemical analysis showed neural rosettes characteristic of COs and shows that neurons, astrocytes and microglia were all present in MCOs throughout development.ConclusionWe have developed a novel model for DS‐AD that will be critical for identifying APOE4‐microglial interactions as a therapeutic target in DS‐AD. These MCOs may be used in pre‐clinical testing of potential therapies, which may lead to treatment for the highly vulnerable population of APOE4 carriers with DS‐AD.

The association of body composition and fat distribution with dysmobility syndrome in community-dwelling older adults: Bushehr Elderly Health (BEH) program

Background and objectiveDysmobility Syndrome (DS) is characterized as an accumulation of clinical risk factors for functional disability, such as osteoporosis, sarcopenia, and obesity. Neurological disorders that affect the motor and sensory systems can also contribute to the condition, resulting in gait and muscle strength disturbances, as well as a history of falls and fractures. The study aimed to determine the association between fat distribution in different body areas and the odds of older adults developing DS, as there is still uncertainty about the accumulation of fat in which area is most closely linked to the condition.MethodsThis cross-sectional study was conducted according to the data from the second phase of the Bushehr Elderly Health Cohort (BEH). Dysmobility Syndrome was defined based on the co-occurrence of at least three outcomes of its criteria. Body composition was measured using dual-energy X-ray absorptiometry (DXA) and anthropometric studies. For evaluating the relationship, multivariate logistic regression and adjusted univariate linear regression were used.ResultsOf 2,359 who were recruited in the study, 1,277 participants (54.13%) had DS. According to the final logistic regression model in the limb region, FM and FM to FFM ratios were significantly associated with DS [OR (95%CI) = 1.04 (1.02 to 1.05), and 3.42 (1.95 to 5.99), respectively]. Also, In the trunk region, the FM and FM to FFM ratio were significantly related to the odds of DS, although this relationship was weaker than in the limbs region [OR (95%CI) = 1.02 (1.00 to 1.03), and 2.45 (1.36 to 4.39), respectively].ConclusionOur findings indicate that a higher regional and whole-body amount of fat mass rather than fat-free mass is closely linked to an increased risk of DS, particularly in the elderly population. Notably, higher fat mass in the limbs (especially in the legs) is associated with greater odds of DS, while a higher android-to-gynoid fat mass ratio is associated with lower DS risk. Screening fat mass distribution in older individuals can be a valuable strategy for promptly diagnosing DS, implementing interventions to prevent disabilities, and improving their quality of life.

Demographic and biochemical risk factors of Down Syndrome in pregnant women: A pilot study in Sylhet division of Bangladesh

Worldwide research in down syndrome have shown that advanced maternal age (˃30 years) at conception, lower folate status and/or impaired folate metabolism, maternal weight gain during pregnancy, low socioeconomic conditions, radiation exposure, use of contraceptive pills, and taking tobacco/smoking are major maternal risk factors for giving birth child with DS. However, the occurrence of those factors in pregnant women at advanced age has not yet been investigated in Bangladesh. Therefore, a large scale study was needed to explore the overall scenario in Bangladesh. This pilot cross sectional study was aimed to determine the serum folate and homocysteine status at advanced age pregnant women. We measured serum folate and homocysteine concentrations using the Enzyme-Linked Immunosorbent Assay (ELISA). Out of 70 pregnant women, serumfolate level was low (<5 ng/ml) in 13 (18.57%), intermediate (5-6.9 ng/ml) in 8 (11.43%) and normal in 49 (70%) whereas homocysteine concentrations were found low (<5 ng/ml) in all participants. Finally, questionnaire data indicates, low socioeconomic status, overweight during pregnancy, taking contraceptive pills and taking tobacco/smoking was higher percentage in folate-deficient pregnant women than normal serum folate level women. Additionally, women (n=13) with low folate level belongs to low socioeconomic status, overweight, taking contraceptive pills and tobacco/smoking did not give birth child with DS phenotypes. Together, our preliminary findings give an overview of DS associated risk factors in Bangladeshi pregnant women. Large scale study is going on. In next study, we might able to investigate DS risk factors, their associations with serum folate and homocysteine levels and finally with DS phenotypes in child throughout the country. Keywords: Down syndrome; risk factors; folic acid; homocysteine; pregnant women; Bangladesh.

A machine learning model for the prediction of down syndrome in second trimester antenatal screening

BackgroundDown syndrome (DS) is the most common human chromosomal abnormality. About 1200 laboratories carry out antenatal screening for DS in second trimester pregnancies in China. Their prenatal assessment of DS pregnancy risk is based on biometric calculations conducted on maternal serum biochemical markers and ultrasonic markers of fetal growth. However, the performance of this triple test for DS in second trimester pregnancies has a false positive rate of 5%, and a detection rate of about 60%∼65%. MethodA total of 58,972 pregnant women, including 49 DS cases, who had undergone DS screening in the second trimester were retrospectively included and a machine learning (ML) model based on random forest was built to predict DS. In addition, the model was applied to another hospital data set of 27,170 pregnant women, including 27 DS cases, to verify the predictive efficiency of the model. ResultsThe ML model gave a DS detection rate of 66.7%, with a 5% false positive rate in the model data set. In the external verification data set, the ML model achieved a DS detection rate of 85.2%, with a 5% false positive rate . In comparison with the current laboratory risk model, the ML model improves the DS detection rate with the same false positive rate, while the difference has no significance. ConclusionsThe ML model for DS detection described here has a comparable detection rate with the same false positive rate as the DS risk screening software currently used in China. Our ML model exhibited robust performance and good extrapolation, and could function as an alternative tool for DS risk assessment in second trimester maternal serum.

The Population Prevalence, Associations of Congenital Heart Defect and Mortality Risk for Down's Syndrome in South Korea Based on National Health Insurance Service (NHIS) Data.

BackgroundIn the present study, we estimated the population prevalence, associations of congenital heart defect (CHD) and mortality risk for DS using data from National Health Insurance Service (NHIS) and Rare Diseases Registry (RDR).MethodsWe collected data on subjects with DS who were registered in the RDR between 2010 and 2015. To estimate associations of CHD and mortality risk of DS, the data of DS subjects were compared with 1:5 age- and sex-matched controls.ResultsIn 2015, 2077 individuals with DS were identified out of the total population of 51,574,044 South Koreans and the prevalence was 4.03 per 100,000 persons. The trend of DS population prevalence across 10-year-old intervals showed a peak in the group under the age of 10 years (26.0 per 100,000 persons) and then declined sharply after the age of 20 years (0.98 per 100,000 persons at 30–39 years of age). In subjects with DS, the frequencies of atrial septal defect [odds ratios (OR) =65.9; 95% CI, 84.1–99.1], ventricular septal defect (OR = 88.1, 95% CI, 57.9–134.1), patent ductus arteriosus (OR = 56.9, 95% CI, 40.1–80.8), tetralogy of fallot (OR = 42.1, 95% CI, 19.3–92.3), or atrioventricular septal defect (OR = 510.0, 95% CI, 126.7–999.0) were higher than those of age- and sex-matched controls. The risk of death in patients with DS was significantly higher than that of age- and sex-matched controls [hazard ratio (HR) =41.7, 95% CI 20.0–87.0].ConclusionIn South Korea, the DS population prevalence was 4.03 per 100,000 persons in 2015. The subjects with DS were more likely to accompany CHD and have higher mortality risk than healthy controls.

Depressive symptoms during pregnancy and their risk factors – a cross-sectional study

Introduction. It was established that intragestational depression is a common disease, with the estimated average prevalence of 10–25% in all expectant mothers worldwide. Aim of the study. The aim of the study was to evaluate the frequency of depressive symptoms in pregnant women in Poland and to identify which factors may be related to a higher risk of depressive symptoms during pregnancy. Material and methods. A prospective cross-sectional study was performed. Depressive symptoms were assessed with the validated Edinburgh Postnatal Depression Scale (EPDS). 346 women were enrolled in the study. Results. 130 women (37.6%) scored 13 or more points and were considered as presenting with depressive symptoms. Independent risk factors of depressive symptoms during pregnancy including mood disorders diagnosed before the current pregnancy (aOR=2.68, 95%CI 1.37-5.22), mental disorders confirmed in family members (aOR=2.72, 95%CI 1.24-5.98), unhappiness in their current relationship (aOR=4.0, 95%CI 1.77-9.01), lack of support from family members (aOR=2.73, 95%CI 1.51-4.96) increased the risk of DS and good financial status decreased the risk of DS occurrence (aOR=0.45, 95%CI: 0.25-0.80). Conclusions. Pregnant women commonly report depressive symptoms. The evaluation of relations with the family members, socio-economic status, former depressive symptoms and possible prenatal depression are essential for proper screening of depression in pregnant women.

CORRELATION OF UPPER AND LOWER EXTREMITIES ISOKINETIC STRENGTH IN ELITE MALE

Background and purposeMuscle strength is one of the most physically important parameters during the competition for judokas. Studies have shown that for judokas, strength in especially the knee and shoulder muscles and the strength balance between right and left sides is very important in terms of both staying in balance and doing spe-cific techniques correctly. Our study aims to find out the correlations between isokinetic lower and upper extremity strength in elite judokas and to examine bilateral and contralateral strength ratios. MethodsThis study is designed according to cross-experimental design with randomized repeated measurements. Fifteen male (mean values: age 19.40 ± 1.24 years, height 170.55 ± 9.44 cm, weight 78.47 ± 18.55 kg, and BMI 27.02 ± 5.82 kg/m2) elite judokas between the ages of 18 and 21 participated voluntarily in the study. Knee extension (EX) and flexion (FLX), shoulder internal rotation (IR) and external rotation (ER) isoki-netic strength measurements of the subjects were measured with concentric/concentric (Con/Con) con-tractions at 60o s-1 and 180o s-1 angular velocities. Ipsilateral hamstring/quadriceps (H/Q), internal rotation/external rotation (IR/ER), contralateral Q/Q, H/H, IR/IR, ER/ER ratios were calculated through lower and upper extremity isokinetic strength. Shapiro–Wilk, Levene, paired sample t-test, and Pearson correlation test were used in statistical analyses. ResultsIn terms of the ipsilateral strength ratios on dominant (DS) and nondominant (NDS) in lower and upper extremities, a significant difference was found only at 60° s-1 angular velocity in only the lower extremity on DS (P 0.05). High correlations were found between all other parameters (P > 0.05). ConclusionsIn conclusion, it was found that lateral asymmetric ratios may differ in elite judokas especially at low angu-lar velocities; however, this difference was not at a level to cause the risk of injury, DS and NDS showed similar strength in both lower and upper extremity, and there were high positive correlations between lower and upper extremity strength.

Sleep problems and associations with psychopathology and cognition in young people with 22q11.2 deletion syndrome (22q11.2DS).

Young people with 22q11.2 deletion syndrome (22q11.2DS) are at high risk for neurodevelopmental disorders. Sleep problems may play a role in this risk but their prevalence, nature and links to psychopathology and cognitive function remain undescribed in this population. Sleep problems, psychopathology, developmental coordination and cognitive function were assessed in 140 young people with 22q11.2DS (mean age = 10.1, s.d. = 2.46) and 65 unaffected sibling controls (mean age = 10.8, s.d.SD = 2.26). Primary carers completed questionnaires screening for the children's developmental coordination and autism spectrum disorder. Sleep problems were identified in 60% of young people with 22q11.2DS compared to 23% of sibling controls (OR 5.00, p < 0.001). Two patterns best-described sleep problems in 22q11.2DS: restless sleep and insomnia. Restless sleep was linked to increased ADHD symptoms (OR 1.16, p < 0.001) and impaired executive function (OR 0.975, p = 0.013). Both patterns were associated with elevated symptoms of anxiety disorder (restless sleep: OR 1.10, p = 0.006 and insomnia: OR 1.07, p = 0.045) and developmental coordination disorder (OR 0.968, p = 0.0023, and OR 0.955, p = 0.009). The insomnia pattern was also linked to elevated conduct disorder symptoms (OR 1.53, p = 0.020). Clinicians and carers should be aware that sleep problems are common in 22q11.2DS and index psychiatric risk, cognitive deficits and motor coordination problems. Future studies should explore the physiology of sleep and the links with the neurodevelopment in these young people.

Alkaline phosphatase ınterference in an unconjugated estriol assay causing a false positive Down syndrome screening result

Abstract Objective Decreased unconjugated estriol (uE3) concentrations increase calculated risk of Down syndrome. Therefore, falsely low uE3, due to assay interference, have the potential to cause false-positive screening results. Here we present a 35 years old woman with a pregnancy of 17+2 weeks. Materials and methods Second-trimester screening test was performed on the UniCelDxI 800 (Beckman Coulter, Brea, CA, USA) analyzer and her uE3 level was 0.21 ng/mL (0.21 MoM). Risk calculated for DS was 1/8. Measurements were repeated on IMMULITE 2000 XPi (Siemens Healthcare Diagnostics Inc., USA). uE3 result was 0.614 ng/mL (0.97 MoM). The risk for DS was negative with this system. There was no sign of fetal anomaly on three-dimensional ultrasound examination and cell-free fetal DNA screening test. We suspected assay interference for uE3. Results Serial dilutions of serum samples revealed nonlinearity. 36.3% increase was observed with heterophile antibody blocking tubes. The post-polyethylene glycol treatment resulted approximately the same uE3 levels as IMMULITE system. Addition of alkaline phosphatase Scavenger to serum increased the result by 90% showing that falsely low E3 result was due to an interferent reacting on assay medium. Conclusion Laboratories should be aware that falsely low uE3 results due to interference may be obtained.

Dravet syndrome in South African infants: Tools for an early diagnosis

PurposeDravet syndrome (DS) is a well-described, severe genetic epileptic encephalopathy with an increased risk of SUDEP. The incidence and genetic architecture of DS in African patients is virtually unknown, largely due to lack of awareness and unavailability of genetic testing. The clinical benefits of the available precision medicine approaches to treatment emphasise the importance of an early, correct diagnosis. We investigated the genetic causes and clinical features of DS in South African children to develop protocols for early, cost-effective diagnosis in the local setting. MethodWe selected 22 South African children provisionally diagnosed with clinical DS for targeted resequencing of DS-associated genes. We sought to identify the clinical features most strongly associated with SCN1A-related DS, using the DS risk score and clinical co-variates under various statistical models. ResultsDisease-causing variants were identified in 10 of the 22 children: nine SCN1A and one PCDH19. Moreover, we showed that seizure onset before 6 months of age and a clinical DS risk score of >6 are highly predictive of SCN1A-associated DS. Clinical reassessment resulted in a revised diagnosis in 10 of the 12 variant-negative children. ConclusionThis first genetic study of DS in Africa confirms that de novo SCN1A variants underlie disease in the majority of South African patients. Affirming the predictive value of seizure onset before 6 months of age and a clinical DS risk score of >6 has significant practical implications for the resource-limited setting, presenting simple diagnostic criteria which can facilitate early correct treatment, specialist consultation and genetic testing.

Neuroimaging and clinical features in adults with a 22q11.2 deletion at risk of Parkinson's disease.

The recurrent 22q11.2 deletion is a genetic risk factor for early-onset Parkinson's disease. Adults with the associated 22q11.2 deletion syndrome (22q11.2DS) may exhibit phenotypes that could help identify those at highest risk and reveal disease trajectories. We investigated clinical and neuroimaging features relevant to Parkinson's disease in 26 adults: 13 with 22q11.2DS at genetic risk of Parkinson's disease (mean age = 41.5 years, standard deviation = 9.7), 12 healthy age and sex-matched controls, and a 22q11.2DS patient with l-DOPA-responsive early-onset Parkinson's disease. Neuroimaging included transcranial sonography and positron emission tomography using 11C-dihydrotetrabenazine (11C-DTBZ), a radioligand that binds to the presynaptic vesicular monoamine transporter. The 22q11.2DS group without Parkinson's disease demonstrated significant motor and olfactory deficits relative to controls. Eight (61.5%) were clinically classified with parkinsonism. Transcranial sonography showed a significantly larger mean area of substantia nigra echogenicity in the 22q11.2DS risk group compared with controls (P = 0.03). The 22q11.2DS patient with Parkinson's disease showed the expected pattern of severely reduced striatal 11C-DTBZ binding. The 22q11.2DS group without Parkinson's disease however showed significantly elevated striatal 11C-DTBZ binding relative to controls (∼33%; P < 0.01). Results were similar within the 22q11.2DS group for those with (n = 7) and without (n = 6) psychotic illness. These findings suggest that manifestations of parkinsonism and/or evolution to Parkinson's disease in this genetic at-risk population may include a hyperdopaminergic mechanism. Adequately powered longitudinal studies and animal models are needed to evaluate the relevance of the observed clinical and imaging phenotypes to Parkinson's disease and other disorders that are more prevalent in 22q11.2DS, such as schizophrenia.

Association of RFC1 A80G gene polymorphism with advanced maternal age in risk of Down syndrome

BackgroundDown syndrome (DS) is a serious intellectually disabled condition and a major public health concern. Advanced maternal age and altered recombination are the well established factors for its cause. Epidemiological studies have reported conflicting results regarding the association between maternal folate gene polymorphism, folic acid supplementation and the risk of DS. Aim of the studyThe investigation present a case–control study of polymorphisms in four genes (MTHFR C677T, MTHFR A1298C, MTRR A66G, MTR A2756G and RFC1 A80G) involved in folate pathway and assessment of folate supplementation and association of age during conception. Materials and methodsWe investigated 148 DS mothers and 130 control mothers from India. Allele specific primers were used for the analysis of gene polymorphisms, and folic acid supplementation profile was also recorded. ResultsAssociation of RFC1 80GG genotype (3.2579, 95% CI: 1.5363–6.9086, p=0.0021) with DS indicating increased risk in developing DS. A significant association was also found between maternal age of ≥34 years and RFC1 80G alleles in developing DS. Folic acid supplementation profile indicated non-supplementation of folic acid preconception leads to an increase (1.6904, 95% CI: 1.0730–2.6631, p=0.0236) in risk of DS. ConclusionThe present investigation suggests the potential role of RFC1 gene polymorphism in folate metabolism in association with maternal age and dietary folate deficiency preconception increases the risk of DS.

Methionine synthase A2756G and reduced folate carrier1 A80G gene polymorphisms as maternal risk factors for Down syndrome in Egypt

BackgroundPolymorphisms of genes encoding enzymes involved in folate metabolism have long been hypothesized to be maternal risk factors for Down syndrome, however, results are conflicting and inconclusive. Aim of the studyTo analyze the effect of methionine synthase (MTR) A2756G, and reduced folate carrier (RFC1) A80G gene polymorphisms on the maternal risk for DS. PatientsThis study was conducted in the Medical Genetics Center, Ain-Shams University hospitals, on a total of 170 mothers of children, diagnosed with Down syndrome, who were attending the center. Eighty-five control mothers were also enrolled in the study. MethodsGenotype analyses were performed using PCR-RFLP to detect RFC1A80G and MTRA2756G gene polymorphisms in all case and control mothers. ResultsComparing RFC1A80G genotype frequency between both groups revealed, that the frequency of the AA genotype in case mothers (94.11%) is highly significantly (p<0.001) greater than its frequency in control mothers (74.11%), with no significant difference between the two groups regarding GG genotype. Comparing RFC1 A80G allele frequency between the two groups revealed a high frequency of the A allele among case mothers (94.11%), which showed a highly statistically significant difference (p<0.001) from the control group (55.29%), meanwhile the G allele showed a low frequency of 5.88% in DS mothers compared to 22.35% in the control mothers, with a highly statistically significant difference (p<0.001) between the two groups. Regarding MTRA2756G polymorphism, it was found that the AA genotype predominated in the control group (65.88%) with a highly statistically significant difference (p<0.001) from case mothers group (5.88%). Comparing MTR allele frequency between the two groups revealed predominance of the G allele among mothers of DS children (76.47%). ConclusionCurrent results provide strong evidence that the MTRA2756G, and RFC1 80 A genotypes could be considered as maternal risk factors for DS in Egyptian mothers.

The limited effect of information on Israeli pregnant women at advanced maternal age who decide to undergo amniocentesis.

BackgroundA primary goal of amniocentesis is the detection of trisomy 21 (Down syndrome- DS) in the fetus. This procedure involves a small risk of miscarriage. As the risk of DS increases with maternal age, screening tests (maternal serum triple test and others) and age are used to generate a risk assessment, and amniocentesis is offered to women with high risk. In Israel, amniocentesis is government funded for women of advanced maternal age (AMA, i.e., ≥35 years), even if their risk assessment is low.The purpose of this study was to explore the reasons AMA women undergo amniocentesis, their knowledge about risk estimates, and to evaluate whether their decision is informed.MethodsShortly after undergoing amniocentesis, 42 consecutive women without a medical indication for amniocentesis other than age, completed a questionnaire that assessed their knowledge and opinions regarding screening tests, pregnancy termination, amniocentesis risks and the factors that affected their decision.ResultsWomen rarely deliberated before undergoing amniocentesis. One third of those who had the screening test did not wait for the results before undergoing amniocentesis. Only one third of those who received the screening results remembered their risk estimation before going ahead with amniocentesis. Almost half (41 %) cited “age” as their main reason for undergoing amniocentesis, though only 44 % of these women could recall their age related DS risk. Sixty percent estimated their DS risk as low or very low but still had amniocentesis. Most participants (74 %) stated that they would consider termination of the pregnancy if the fetus was diagnosed with an intellectual deficit.ConclusionsThese results cast doubt on whether AMA women’s decision to undergo amniocentesis is based on risk estimates, as women seem to disregard risk estimates, and sometimes not even wait for them when making the decision. The policy of funding amniocentesis solely on the basis of age may have led to the conception that being over 35 alone is sufficient reason to undergo amniocentesis. This finding should inform policy makers, as it raises questions about the link between public funding and the choices of individual women, and has implications for healthcare expenditures.

Altered LINE-1 Methylation in Mothers of Children with Down Syndrome.

Down syndrome (DS, also known as trisomy 21) most often results from chromosomal nondisjunction during oogenesis. Numerous studies sustain a causal link between global DNA hypomethylation and genetic instability. It has been suggested that DNA hypomethylation might affect the structure and dynamics of chromatin regions that are critical for chromosome stability and segregation, thus favouring chromosomal nondisjunction during meiosis. Maternal global DNA hypomethylation has not yet been analyzed as a potential risk factor for chromosome 21 nondisjunction. This study aimed to asses the risk for DS in association with maternal global DNA methylation and the impact of endogenous and exogenous factors that reportedly influence DNA methylation status. Global DNA methylation was analyzed in peripheral blood lymphocytes by quantifying LINE-1 methylation using the MethyLight method. Levels of global DNA methylation were significantly lower among mothers of children with maternally derived trisomy 21 than among control mothers (P = 0.000). The combination of MTHFR C677T genotype and diet significantly influenced global DNA methylation (R2 = 4.5%, P = 0.046). The lowest values of global DNA methylation were observed in mothers with MTHFR 677 CT+TT genotype and low dietary folate. Although our findings revealed an association between maternal global DNA hypomethylation and trisomy 21 of maternal origin, further progress and final conclusions regarding the role of global DNA methylation and the occurrence of trisomy 21 are facing major challenges.

Cytogenetic variations in a series of cases of Down Syndrome

IntroductionDown Syndrome (DS) is generally associated with mental retardation and developmental delay. The occurrence of DS is associated with multiple factors like maternal age, consanguineous marriage, early induced abortion etc. Chances of recurrences of DS in next pregnancy depend on the genetic constitution of the affected individual and the parents. So this study was done to find out the different types of cytogenetic abnormalities in DS patients and also the association of parental age to DS in a population in West Bengal. It is hoped that the present study will emphasize the need for genetic counseling of prospective parents as well as parents of individuals affected with DS, together with cytogenetic screening of pregnancies which are at high risk for DS. MethodsA cytogenetic analysis was performed using conventional GTG banding on 120 patients with clinical features of DS, referred to the Department of Genetics, Vivekananda Institute of Medical Sciences, Kolkata during the period from October, 2008 to September, 2014. ResultsCytogenetic analysis confirmed the diagnosis of DS in 117 cases, among them regular trisomy constituted 83.76%, mosaicism recorded in 11.11% and Robertsonian translocation in 5.12% of cases. The mean maternal age was higher in regular trisomy 21 (25.08 yrs) than in translocation (22.50 yrs). No significant difference was noted in mean paternal age among different categories of DS cases. DiscussionThis study documents the types of cytogenetic abnormalities in DS children of West Bengal population of India and thus emphasizes the need for genetic counseling in these cases.

A Cost-Effectiveness Analysis Comparing Different Strategies to Implement Noninvasive Prenatal Testing Into a Down Syndrome Screening Program

Noninvasive prenatal testing (NIPT) can analyze cell-free DNA of placental origin in maternal serum for trisomy 21. The detection rate is 99.5%, and the false-positive rate (FPR) is 0.2%. Noninvasive prenatal testing is recommended only for highrisk women after conventional screening. Noninvasive prenatal testing is deemed a screening modality, and invasive diagnostic testing is required for confirmation following a “positive” result. The present study was performed to evaluate NIPT by comparing 4 strategies examining cost-effectiveness and budget impacts for health care systems and parturients. A decision-analytic model was created to compare screening-related costs and consequences of NIPT implementation. The first strategy involved current practices using combined first-trimester screening (CFTS) is offered to all women at 11 to 13 weeks’ gestation. Women at high risk for DS are offered invasive diagnostic testing, via amniocentesis with fluorescence in situ hybridization and karyotyping. For strategy 2, NIPT is a second investigation after high-risk CFTS stratification. It was assumed that only women with a positive NIPT undergo invasive diagnostic testing and further counseling. Strategies 3A and 3B categorize women as high or low risk. Women 35 years or older are considered high risk and are initially offered NIPT; all others are offered CFTS, and only those considered at high risk for DS undergo NIPT. All women who are NIPT positive are referred for invasive diagnostic testing. In strategy 4, universal NIPT replaces CFTS with NIPT as the primary screening modality. All women with a positive NIPT undergo invasive diagnostic testing and counseling. Estimated costs for each strategy were those directly related to screening and accruing to government agencies and out-of-pocket costs to the woman. Outcomes included the number of DS cases detected and the number of procedure-related losses (PRLs) avoided by not performing invasive diagnostic testing. Two cost estimates for each strategy were calculated. The low estimate included costs to the health system and patients based on the current Medicare Benefits Schedule cost and the lowest estimate of patient outof-pocket costs; the high estimate was based on both Medicare costs and the highest estimates of private health care prices. Universal NIPT was the most effective strategy and detected 657 DS cases, resulting in 11 PRLs. Strategies 3A and 3B (maternal ages >35 and >40 years, respectively) were more effective than current practices for detecting DS and avoiding PRLs. Strategy 2 was less effective for DS detection, but more effective in avoiding PRLs. Five to 11 PRLs occurred with the new strategies compared with 101 PRLs for the current practice. Strategy 2 was the least expensive option. Implementing universal NIPT would cost more than 4 times the current expenditures on DS screening. The higher cost estimates were double or triple those of the low cost, with higher out-of-pocket costs for patients. Based on DS detection, the most cost-effective new strategy was 3B. Strategies 3A and 4 offered less value for money compared with current practice. Although strategy 2 was less costly and less effective for DS detection, when based on avoiding PRLs, it was the most cost-effective. Strategy 4 had the highest incremental cost per PRL avoided. The benefits of NIPT are its ability to detect a high percentage of DS cases while decreasing the number of PRLs. These advantages generate higher costs to health systems and parturients. The substitution of NIPT for CFTS would be significantly more expensive. Benefits of replacing CFTS with NIPT include an 18% increase in DS cases detected and a decrease in the overall screening positive rate from 3.8% to less than 0.42%. Additional research is necessary to confirm these results.

MiRNA-mediated risk for schizophrenia in 22q11.2 deletion syndrome.

In humans, the most common genomic disorder is a hemizygous deletion of a 1.5–3 Mb region of chromosome 22q11.2. The resultant 22q11.2 deletion syndrome (22q11.2DS) can affect multiple organ systems, and most notably includes cardiac, craniofacial, and neurodevelopmental defects. Individuals with 22q11.2DS have a 20–25-fold risk of developing schizophrenia compared to individuals from the general population, making 22q11.2DS the strongest known molecular genetic risk factor for schizophrenia. Although the deleted region includes DGCR8, a gene coding for a miRNA processing protein, the exact mechanism by which this deletion increases risk is unknown. Importantly, several lines of evidence suggest that miRNAs may modulate risk for schizophrenia in other, non-22q11.2DS populations. Here we present a theory which mechanistically explains the link between 22q11.2DS, miRNAs, and schizophrenia risk. We outline the testable predictions generated by this theory and present preliminary data in support of our model. Further experimental validation of this model could provide important insights into the etiology of both 22q11.2DS and more common forms of schizophrenia.

OP01.09: Nasal bone evaluation in prenatal screening for trisomy 21: a review

Objective: To evaluate the interobserver variability on the subjective assessment of the hypoplastic NB and thickened Nbr used to screen for DS after 18 weeks in women at increased risk for this aneuploidy. Methods: Images of facial profiles for true DS cases were compared to controls without DS. From Oct/03 all cases with images of facial profiles were matched to randomly selected controls having a similar initial risk for DS. The subjective assessment was for a severely hypoplastic/absent NB and if the Nbr was thickened as defined by Nbr tissue that entirely buried the underlying NB. Coded images were independently evaluated by three MFM specialists. Each image was assessed for adequacy of the profile and then for the NB and Nbr. Responses were evaluated using Cohen’s kappa. Results: 118 images were assessed, of which 31 were eliminated due to inadequate image profiles. All examiners agreed on inadequate profiles. Among the 87 cases studied, 22 had DS and 65 were normal controls.

First-Trimester Down Syndrome Screening: Component Analytes and Timing for Optimal Performance

The most effective first-trimester Down syndrome screening protocol in current use employs three independent markers: maternal serum levels of PAPP-A and free beta hCG, and measurement of fetal nuchal translucency (NT). Eleven weeks appears to be the optimum gestational age for performing first trimester DS risk assessment. Although the discrimination of free beta hCG improves with increasing gestational age and is greatest at 13 weeks, PAPP-A and NT perform optimally at 10 and 11 weeks, respectively. In addition to accurate pregnancy dating, first trimester screening performance is improved by using a consistent NT measurement technique, NT cut-offs adjusted for gestational age or crown-rump length, and possibly center- or operator-specific NT medians. Whether or not absence or presence of the nasal bone adds to screening accuracy is a matter of some debate. Finally, because enlarged NT has been associated with cardiac defects and other structural anomalies, even in euploid fetuses, its presence should prompt a targeted second trimester ultrasound examination.