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An accurate accounting of persons with Down syndrome (DS) has remained elusive because no population-based registries exist in the United States. The purpose of this study was to estimate this population size by age, race, and ethnicity. We predicted the number of people with DS in different age groups for different calendar years using estimations of the number of live births of children with DS from 1900 onward and constructing DS-specific mortality rates from previous studies. We estimate that the number of people with DS living in the United States has grown from 49,923 in 1950 to 206,366 in 2010, which includes 138,019 non-Hispanic whites, 27,141 non-Hispanic blacks, 32,933 Hispanics, 6,747 Asians/Pacific Islanders, and 1,527 American Indians/American Natives. Population prevalence of DS in the United States, as of 2010, was estimated at 6.7 per 10,000 inhabitants (or 1 in 1,499). Until 2008, DS was a rare disease. In more recent decades, the population growth of people with DS has leveled off for non-Hispanic whites as a consequence of elective terminations. Changes in childhood survival have impacted the age distribution of people with DS, with more people in their fourth, fifth, and sixth decades of life. Genet Med19 4, 439–447.

Human nondisjunction errors in oocytes are the leading cause of pregnancy loss, and for pregnancies that continue to term, the leading cause of intellectual disabilities and birth defects. For the first time, we have conducted a candidate gene and genome-wide association study to identify genes associated with maternal nondisjunction of chromosome 21 as a first step to understand predisposing factors. A total of 2,186 study participants were genotyped on the HumanOmniExpressExome-8v1-2 array. These participants included 749 live birth offspring with standard trisomy 21 and 1,437 parents. Genotypes from the parents and child were then used to identify mothers with nondisjunction errors derived in the oocyte and to establish the type of error (meiosis I or meiosis II). We performed a unique set of subgroup comparisons designed to leverage our previous work suggesting that the etiologies of meiosis I and meiosis II nondisjunction differ for trisomy 21. For the candidate gene analysis, we selected genes associated with chromosome dynamics early in meiosis and genes associated with human global recombination counts. Several candidate genes showed strong associations with maternal nondisjunction of chromosome 21, demonstrating that genetic variants associated with normal variation in meiotic processes can be risk factors for nondisjunction. The genome-wide analysis also suggested several new potentially associated loci, although follow-up studies using independent samples are required.

Background Children with Down Syndrome (DS) are more likely to have multi-system comorbidities leading to more frequent hospitalizations than the general population. We aim to evaluate whether racial differences contribute to hospitalization outcomes and mortality among children with DS. Methods Hospital discharge records were obtained for children (< 21 y) with DS hospitalized between 2006 and 2019 from the Kid’s Inpatient Database. The primary exposure was the Black race. Primary outcomes were invasive mechanical ventilation (IMV) and mortality. Secondary outcomes were non-invasive mechanical ventilation (NIMV), length of hospital stay (LOS), and inflation-adjusted cost of hospitalization (IACH). Multivariable logistic regression models were used to ascertain associations between Black race and outcomes. Results Among 163,870 hospitalizations in children with DS, 16,208 (9.89%) were Black children. Compared with non-Black children, Black children were younger, of lower household incomes, more likely to have public insurance, more likely to have asthma, OSA, obesity, prematurity, congenital heart disease, pulmonary hypertension, congenital airway anomalies, neuromuscular weakness, and dysphagia. Descriptive analyses indicated that Black race was associated with higher risks of mortality, IMV, NIMV, longer LOS, and greater IACH. After multivariable adjustment, Black race remained independently associated with mortality (OR:1.35, 95%-CI:1.15–1.59, p  < 0.0001), IMV (OR:1.34, 95%-CI:1.23–1.45, p  < 0.0001), NIMV (OR:1.41, 95%-CI:1.26–1.59, p  < 0.0001) and increased LOS (IRR:1.08, 95%-CI:1.04–1.13, p  < 0.0001), but not IACH. Conclusions Hospitalized Black children with DS are more likely to be younger, of lower household incomes, with public insurance, and with other underlying comorbidities. Black children had increased risks of mortality and IMV and increased LOS.

This study investigated mortality and causes of death between 1988 and 1999 in 14781 persons (6702 female) with Down syndrome in California, comparing age, sex, ethnicity, and other factors. Mean age at the start of follow-up was 14 years 8 months (SD 14y 10mo). During the study period 600 persons died. The standardized mortality ratio (SMR) for the population was 5.5. Blacks were at greater risk than whites, Hispanics, or Asians (relative risk=1.5). Mortality declined during the period, especially for children with congenital heart defects. Leukemia (SMR=17), respiratory illnesses (SMR=27), congenital anomalies (SMR=72), and circulatory diseases (SMR=5.3) accounted for most of the excess mortality. With the exception of leukemia, cancer mortality was not different from that of the general population.

One in five people with Down syndrome (DS) are born with an atrioventricular septal defect (AVSD), an incidence 2000 times higher than in the euploid population. The genetic loci that contribute to this risk are poorly understood. In this study, we tested two hypotheses: (1) individuals with DS carrying chromosome 21 copy number variants (CNVs) that interrupt exons may be protected from AVSD, because these CNVs return AVSD susceptibility loci back to disomy, and (2) individuals with DS carrying chromosome 21 genes spanned by microduplications are at greater risk for AVSD because these microduplications boost the dosage of AVSD susceptibility loci beyond a tolerable threshold. We tested 198 case individuals with DS+AVSD, and 211 control individuals with DS and a normal heart, using a custom microarray with dense probes tiled on chromosome 21 for array CGH (aCGH). We found that neither an individual chromosome 21 CNV nor any individual gene intersected by a CNV was associated with AVSD in DS. Burden analyses revealed that African American controls had more bases covered by rare deletions than did African American cases. Inversely, we found that Caucasian cases had more genes intersected by rare duplications than did Caucasian controls. We also showed that previously DS+AVSD (DS and a complete AVSD)-associated common CNVs on chromosome 21 failed to replicate. This research adds to the swell of evidence indicating that DS-associated AVSD is similarly heterogeneous, as is AVSD in the euploid population.

To establish normative weight-adjusted models for the median levels of first trimester serum biomarkers for trisomy 21 screening in southern Thai women, and to compare these reference levels with Caucasian-specific and northern Thai models. A cross-sectional study was conducted in 1,150 normal singleton pregnancy women to determine serum pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG) concentrations in women from southern Thailand. The predicted median values were compared with published equations for Caucasians and northern Thai women. The best-fitting regression equations for the expected median serum levels of PAPP-A (mIU/L) and free β- hCG (ng/mL) according to maternal weight (Wt in kg) and gestational age (GA in days) were: [Formula: see text] and [Formula: see text] Both equations were selected with a statistically significant contribution (p< 0.05). Compared with the Caucasian model, the median values of PAPP-A were higher and the median values of free β-hCG were lower in the southern Thai women. And compared with the northern Thai models, the median values of both biomarkers were lower in southern Thai women. The study has successfully developed maternal-weight- and gestational-age-adjusted median normative models to convert the PAPP-A and free β-hCG levels into their Multiple of Median equivalents in southern Thai women. These models confirmed ethnic differences.

Background: Children with Down syndrome (DS) have a higher prevalence of obesity than other children. Whether this increased risk for obesity is due to a lower resting energy expenditure (REE) is controversial. Our study assessed whether (1) the REE of children with DS adjusted for fat-free mass (FFM) was lower than that of sibling controls, and (2) the changes in fat mass (FM) over 3 years were associated with FFM-adjusted baseline REE. Methods: This study used cross-sectional and prospective cohort designs. Four annual measurement visits were conducted with 28 children with DS and 35 sibling controls aged 3–10years. REE and serum thyroxine (T4) were measured at baseline. Anthropometry, skinfold thickness measures, and, in a subsample, dual-energy x-ray absorptiometry (DXA) were used at each visit to calculate FM. Results: Children with DS had significantly lower REE adjusted for FFM (−78 kcal/day, 95% CI: −133 to −27, P =0.003). The difference remained significant after adjustment for FM, sex and African ancestry (−49 kcal/day, 95% CI: −94 to −4, P =0.03). In the longitudinal analysis, the baseline REE adjusted for baseline FFM was not predictive of FM accretion over time ( P =0.8). Conclusion: Children with DS have lower REE than sibling controls, but REE was not associated with changes in FM over time. The results suggest that the lower REE of children with DS does not explain their increased risk for obesity.

Objective We aimed to conduct an analysis of the associations between the information provision procedure of prenatal screening for Down’s syndrome and congenital anomalies and the intention to participate in prenatal screening (PS) of ethnicity groups and Dutch language proficiency groups. Design Using a prospective web-based registration form, we asked counselors (midwives, general practitioners, nurses and gynecologists) to report whether and how they offered information about PS to pregnant women. Duration The study was conducted from 2008 to 2010. Participants We collected data on the characteristics of the women who received an information offer about PS from counselors. Measurements Measures included socio-demographic and language proficiency level (LPL) characteristics, key elements of the provision procedure of PS, and intentional participation in PS. Findings The dataset represents 37% of the total population in the study area. Women with a non-native Dutch background and/or insufficient Dutch LPL received fewer information offers about PS, faced a reduced chance of receiving counseling, and showed lower intentional participation rates for PS. Key Conclusions Women with a non-native Dutch background and/or with an insufficient LPL are underserved in the Dutch PS program. These findings present evidence indicating that the fundamental principle of the Dutch Population Screening Act, namely, equal access to PS for all pregnant women, is not being realized. Implications for Practice Therefore, the study findings are important for national and international healthcare, policy makers and governmental professionals to allow ethnic and LPL-related differences in the provision and intentional uptake of PS.

Advanced maternal age and altered recombination are known risk factors for Down syndrome cases due to maternal nondisjunction of chromosome 21, whereas the impact of other environmental and genetic factors is unclear. The aim of this study was to investigate an association between low maternal socioeconomic status and chromosome 21 nondisjunction. Data from 714 case and 977 control families were used to assess chromosome 21 meiosis I and meiosis II nondisjunction errors in the presence of three low socioeconomic status factors: (i) both parents had not completed high school, (ii) both maternal grandparents had not completed high school, and (iii) an annual household income of <$25,000. We applied logistic regression models and adjusted for covariates, including maternal age and race/ethnicity. As compared with mothers of controls (n = 977), mothers with meiosis II chromosome 21 nondisjunction (n = 182) were more likely to have a history of one low socioeconomic status factor (odds ratio = 1.81; 95% confidence interval = 1.07–3.05) and ≥2 low socioeconomic status factors (odds ratio = 2.17; 95% confidence interval = 1.02–4.63). This association was driven primarily by having a low household income (odds ratio = 1.79; 95% confidence interval = 1.14–2.73). The same statistically significant association was not detected among maternal meiosis I errors (odds ratio = 1.31; 95% confidence interval = 0.81–2.10), in spite of having a larger sample size (n = 532). We detected a significant association between low maternal socioeconomic status and meiosis II chromosome 21 nondisjunction. Further studies are warranted to explore which aspects of low maternal socioeconomic status, such as environmental exposures or poor nutrition, may account for these results. Genet Med15 9, 698–705.