Research focused on Down syndrome continued to gain momentum in the last several years and is advancing our understanding of how trisomy 21 (T21) modifies molecular and cellular processes. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. During the COVID pandemic, T21RS held its first virtual conference program, sponsored by the University of California at Irvine, on June 8–10, 2021 and brought together 342 scientists, families, and industry representatives from over 25 countries to share the latest discoveries on underlying cellular and molecular mechanisms of T21, cognitive and behavioral changes, and comorbidities associated with Down syndrome, including Alzheimer's disease and Regression Disorder. Presentations of 91 cutting-edge abstracts reflecting neuroscience, neurology, model systems, psychology, biomarkers, and molecular and pharmacological therapeutic approaches demonstrate the compelling interest and continuing advancement toward innovating biomarkers and therapies aimed at ameliorating health conditions associated with T21.

Women who carry an FMR1 (i.e., fragile X) premutation have specific health risks over their lifetime. However, little is known about their experience understanding these risks and navigating their health needs. The aim of this study was to use qualitative analysis to uncover both barriers and facilitators to personal healthcare using a framework of the Health Belief Model. Five focus groups were conducted with a total of 20 women who carry the FMR1 premutation using a semi-structured discussion guide. All sessions were transcribed verbatim and independently coded by two researchers. The coders used a deductive – inductive approach to determine the prominent themes related to the participants’ experiences seeking healthcare for premutation-related conditions. Salient barriers to personal healthcare included difficult clinical translation of research findings, lack of knowledge among healthcare providers and among the women themselves, different priorities, and shortage of premutation-specific support and targeted educational materials. Facilitators included family members, national and community support organizations, research studies, compassionate physicians, and other premutation carriers. Addressing barriers to personal healthcare through up-to-date educational materials can help diminish misperceptions regarding health risks. Targeted educational materials will aid in information sharing and awareness for women who carry the FMR1 premutation and their physicians.

Meiotic recombination is an essential step in gametogenesis, and is one that also generates genetic diversity. Genome-wide association studies (GWAS) and molecular studies have identified genes that influence of human meiotic recombination. RNF212 is associated with total or average number of recombination events, and PRDM9 is associated with the locations of hotspots, or sequences where crossing over appears to cluster. In addition, a common inversion on chromosome 17 is strongly associated with recombination. Other genes have been identified by GWAS, but those results have not been replicated. In this study, using new datasets, we characterized additional recombination phenotypes to uncover novel candidates and further dissect the role of already known loci. We used three datasets totaling 1562 two-generation families, including 3108 parents with 4304 children. We estimated five different recombination phenotypes including two novel phenotypes (average recombination counts within recombination hotspots and outside of hotspots) using dense SNP array genotype data. We then performed gender-specific and combined-sex genome-wide association studies (GWAS) meta-analyses. We replicated associations for several previously reported recombination genes, including RNF212 and PRDM9. By looking specifically at recombination events outside of hotspots, we showed for the first time that PRDM9 has different effects in males and females. We identified several new candidate loci, particularly for recombination events outside of hotspots. These include regions near the genes SPINK6, EVC2, ARHGAP25, and DLGAP2. This study expands our understanding of human meiotic recombination by characterizing additional features that vary across individuals, and identifying regulatory variants influencing the numbers and locations of recombination events.

Individuals with trisomy 21 display complex phenotypes with differing degrees of severity. Numerous reliable methods have been established to diagnose the initial trisomy in these patients, but the identification and characterization of the genetic basis of the phenotypic variation in individuals with trisomy remains challenging. To date, methods that can accurately determine genotypes in trisomic DNA samples are expensive, require specialized equipment and complicated analyses. Here we report proof-of-concept results for an Invader® assay-based genotyping procedure that can determine SNP genotypes in trisomic genomic DNA samples in a simple and cost-effective manner. The procedure requires only two experimental steps: a real-time measurement of the fluorescent Invader® signal and analysis with a specifically designed clustering algorithm. The approach was tested using genomic DNA samples from 23 individuals with trisomy 21, and results were compared to genotypes previously determined with pyrosequencing. Additional assays for 15 SNPs were tested in a set of 21 DNA samples to assess assay performance. Our method successfully identified the correct SNP genotypes for the trisomic genomic DNA samples tested, and thus provides an alternative to determine SNP genotypes in trisomic DNA samples for subsequent association studies in patients with Down syndrome and other trisomies. © 2008 The Author(s).

Neurocognitive assessment in individuals with intellectual disabilities requires a well-validated test battery. To meet this need, the Arizona Cognitive Test Battery (ACTB) has been developed specifically to assess the cognitive phenotype in Down syndrome (DS). The ACTB includes neuropsychological assessments chosen to 1) assess a range of skills, 2) be non-verbal so as to not confound the neuropsychological assessment with language demands, 3) have distributional properties appropriate for research studies to identify genetic modifiers of variation, 4) show sensitivity to within and between sample differences, 5) have specific correlates with brain function, and 6) be applicable to a wide age range and across contexts. The ACTB includes tests of general cognitive ability and prefrontal, hippocampal and cerebellar function. These tasks were drawn from the Cambridge Neuropsychological Testing Automated Battery (CANTAB) and other established paradigms. Alongside the cognitive testing battery we administered benchmark and parent-report assessments of cognition and behavior. Individuals with DS (n=74, ages 7-38 years) and mental age (MA) matched controls (n=50, ages 3-8 years) were tested across 3 sites. A subsample of these groups were used for between-group comparisons, including 55 individuals with DS and 36 mental age matched controls. The ACTB allows for low floor performance levels and participant loss. Floor effects were greater in younger children. Individuals with DS were impaired on a number ACTB tests in comparison to a MA-matched sample, with some areas of spared ability, particularly on tests requiring extensive motor coordination. Battery measures correlated with parent report of behavior and development. The ACTB provided consistent results across contexts, including home vs. lab visits, cross-site, and among individuals with a wide range of socio-economic backgrounds and differences in ethnicity. The ACTB will be useful in a range of outcome studies, including clinical trials and the identification of important genetic components of cognitive disability. © 2010 Springer Science+Business Media, LLC.

Nondisjunction of chromosome 21 is the leading cause of Down syndrome. Two risk factors for maternal nondisjunction of chromosome 21 are increased maternal age and altered recombination. In order to provide further insight on mechanisms underlying nondisjunction, we examined the association between these two well established risk factors for chromosome 21 nondisjunction. In our approach, short tandem repeat markers along chromosome 21 were genotyped in DNA collected from individuals with free trisomy 21 and their parents. This information was used to determine the origin of the nondisjunction error and the maternal recombination profile. We analyzed 615 maternal meiosis I and 253 maternal meiosis II cases stratified by maternal age. The examination of meiosis II errors, the first of its type, suggests that the presence of a single exchange within the pericentromeric region of 21q interacts with maternal age-related risk factors. This observation could be explained in two general ways: 1) a pericentromeric exchange initiates or exacerbates the susceptibility to maternal age risk factors or 2) a pericentromeric exchange protects the bivalent against age-related risk factors allowing proper segregation of homologues at meiosis I, but not segregation of sisters at meiosis II. In contrast, analysis of maternal meiosis I errors indicates that a single telomeric exchange imposes the same risk for nondisjunction, irrespective of the age of the oocyte. Our results emphasize the fact that human nondisjunction is a multifactorial trait that must be dissected into its component parts to identify specific associated risk factors. © 2008 Oliver et al.

Decades of public health research have documented that smoking in pregnancy poses significant health risks to both mother and child. More recent studies have shown that even passive maternal exposure to secondhand smoke associates with negative birth outcomes. However, the mechanisms linking exposure to outcomes have remained obscure. As a first step toward defining the metabolic consequence of low-level nicotine exposure on fetal development, we conducted an untargeted metabolomic analysis of 81 paired samples of maternal serum and amniotic fluid collected from karyotypically normal pregnancies in the second trimester. By comparing the m/z and retention times of our mass spectral features with confirmed standards, we identified cotinine, a nicotine derivative, and used the calculated cotinine concentrations to classify our maternal serum samples into exposure groups using previously defined cut-offs. We found that cotinine levels consistent with low-level maternal exposure to nicotine associated with distinct metabolic perturbations, particularly in amniotic fluid. In fact, the metabolic effects in amniotic fluid of ostensibly low-level exposed mothers showed greater overlap with perturbations previously observed in the sera of adult smokers than did the perturbations observed in the corresponding maternal sera. Dysregulated fetal pathways included aspartate and asparagine metabolism, pyrimidine metabolism, and metabolism of other amino acids. We also observed a strong negative association between level of maternal serum cotinine and acetylated polyamines in the amniotic fluid. Combined, these results confirm that low-level maternal nicotine exposure, indicated by a maternal serum cotinine level of 2–10 ng/mL, is associated with striking metabolic consequences in the fetal compartment, and that the affected pathways overlap those perturbed in the sera of adult smokers.

Background: This is the first description of preventive care services specifically received by children and young adults with fragile X syndrome (FXS). We compare these rates to those of other pediatric populations and identify care disparities within our cohort. Objective: Describe the frequency of preventive care services and health behaviors by young people with FXS, and identify disparities in care. Methods: We assessed four preventive care outcomes and the total number of preventive care guidelines met among individuals under 21 years from the ongoing Fragile X Online Registry with Accessible Research Database (N = 406) using data from 2012 to 2015. We used adjusted odds ratios (AORs) from multiple logistic regression models to describe associations between demographic factors and preventive care outcomes. Results: Seventy-five percent of our sample met dental care guidelines, 55.4% met influenza vaccination guidelines, 92.1% met immunization guidelines, and 24.4% met physical activity (PA) guidelines. Compared to children six to 10 years, younger children were less likely to have seen a dentist as recommended (AOR: 0.26) and young adults aged 16–20 were less likely to have received immunizations (AOR: 0.14) or to have engaged in recommended PA (AOR: 0.29). Black participants (AOR: 0.25) were less likely to have received an influenza vaccination than white participants. Individuals with autism (AOR: 0.25) were less likely to have sufficient PA, while individuals with hypersensitivity were more likely to have sufficient PA (AOR: 2.37) than unaffected individuals. Conclusions: The proportion of young people with FXS that meet basic recommendations in preventive care guidelines varies according to health condition and demographic characteristics. This proportion could be increased for some groups, particularly in the cases of influenza vaccination and physical activity.

Trisomy 21, resulting in Down Syndrome (DS), is the most common autosomal trisomy among live-born infants and is caused mainly by nondisjunction of chromosome 21 within oocytes. Risk factors for nondisjunction depend on the parental origin and type of meiotic error. For errors in the oocyte, increased maternal age and altered patterns of recombination are highly associated with nondisjunction. Studies of normal meiotic events in humans have shown that recombination clusters in regions referred to as hotspots. In addition, GC content, CpG fraction, Poly(A)/Poly(T) fraction and gene density have been found to be significant predictors of the placement of sex-averaged recombination in the human genome. These observations led us to ask whether the altered patterns of recombination associated with maternal nondisjunction of chromosome 21 could be explained by differences in the relationship between recombination placement and recombination-related genomic features (i.e., GC content, CpG fraction, Poly(A)/Poly(T) fraction or gene density) on 21q or differential hot-spot usage along the nondisjoined chromosome 21. We found several significant associations between our genomic features of interest and recombination, interestingly, these results were not consistent among recombination types (single and double proximal or distal events). We also found statistically significant relationships between the frequency of hotspots and the distribution of recombination along nondisjoined chromosomes. Collectively, these findings suggest that factors that affect the accessibility of a specific chromosome region to recombination may be altered in at least a proportion of oocytes with MI and MII errors.

Fragile X-associated primary ovarian insufficiency (FXPOI) occurs in about 20% of women who carry a premutation allele (55-200 CGG repeats). These women develop hypergonadotropic hypogonadism and have secondary amenorrhea before age 40. A non-linear association with repeat size and risk for FXPOI has been seen in multiple studies women with a premutation: those with a mid-range of repeats are at highest risk (~70-100 CGG repeats). Importantly, not all carriers with 70-100 repeats experience FXPOI. We investigated whether AGG interruptions, adjusted for repeat size, impacted age at secondary amenorrhea. We have reproductive history information and AGG interruption data on 262 premutation women: 164 had an established age at amenorrhea (AAA) (for some, age at onset of FXPOI) or menopause, 16 had a surgery involving the reproductive system such as a hysterectomy, and 82 women were still cycling at the last interview. Reproductive status was determined using self-report reproductive questionnaires and interviews with a reproductive endocrinologist. For each of these 262 women, FMR1 repeat size and number of AGG interruptions were determined. We confirmed the association of repeat size with AAA or menopause among women with a premutation. As expected, both premutation repeat size and the quadratic form of repeat size (i.e., squared term) were significant in a survival analysis model predicting AAA (p < 0.0001 for both variables). When number of AGG interruptions was added to the model, this variable was not significant (p = 0.59). Finally, we used a regression model based on the 164 women with established AAA to estimate the proportion of variance in AAA explained by repeat size and its squared term. Both terms were again highly significant (p < 0.0001 for both), but together only explained 13% of the variation in AAA. The non-linear association between AAA and FMR1 repeat size has been described in several studies. We have determined that AGG interruption pattern does not contribute to this association. Because only 13% of the variation is described using repeat size, it is clear that further research of FXPOI is needed to identify other factors that affect the risk for FXPOI.