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Accumulating evidence suggests that circular RNAs (circRNAs)—miRNA–mRNA ceRNA regulatory network—may play an important role in neurological disorders, such as Alzheimer’s disease (AD). Interestingly, neuropathological changes that closely resemble AD have been found in nearly all Down syndrome (DS) cases > 35 years. However, few studies have reported circRNA transcriptional profiling in DS cases, which is caused by a chromosomal aberration of trisomy 21. Here, we characterized the expression profiles of circRNAs in the fetal hippocampus of DS patients (n = 8) and controls (n = 6) by using microarray. MiRNA, mRNA expression profiling of DS from our previous study and scRNA-seq data describing normal fetal hippocampus development (GEO) were also integrated into the analysis. The similarity between circRNAs/genes with traits/cell-types was calculated by weighted correlation network analysis (WGCNA). miRanda and miRWalk2 were used to predict ceRNA network interactions. We identified a total of 7,078 significantly differentially expressed (DE) circRNAs, including 2,637 upregulated and 4,441 downregulated genes, respectively. WGCNA obtained 15 hub circRNAs and 6 modules with cell type–specific expression patterns among scRNA-seq data. Finally, a core ceRNA network was constructed by 14 hub circRNAs, 17 DE miRNA targets and 245 DE mRNA targets with a cell type–specific expression pattern annotation. Known functional molecules in DS or neurodegeneration (e.g., miR-138, OLIG1, and TPM2) were also included in this network. Our findings are the first to delineate the landscape of circRNAs in DS and the first to effectively integrate ceRNA regulation with scRNA-seq data. These data may provide a valuable resource for further research on the molecular mechanisms or therapeutic targets underlying DS neuropathy.

A neonate with a double aneuploidy associ- ated with congenital heart defect (CHD) suffered from cyanosis after birth. He had typical features of Down syndrome (DS) including hypertelorism, slightly lowset ears with protruding pinna. Doppler echocardiography indicated complex congenital heart disease with an ostium secundum atrial septal defect, enlarged right ventricle, and mild tricuspid valve re- gurgitation. Further chromosomal analysis showed a karyotype of 48,XXY,+21: a double aneuploidy of DS and Klinefelter syndrome (KS). Until now, only seven cases of double aneuploidy associated with CHD defect have been reported. Keywords: Double aneuploidy; Down syn dro- me (DS); Klinefelter syndrome (KS); 48,XXY,+21; Congenital heart defect (CHD).

Backgrounds Down syndrome (DS), caused by triplication of human chromosome 21, is the most common aneuploidies. The main characteristic of DS patients is intellectual disability. MicroRNAs (miRNAs) play important regulatory roles in various biological processes, such as embryonic development, cell differentiation, proliferation and apoptosis. Several miRNAs have shown association with DS. However, the role of miRNAs in DS patients has not been well elaborated. Methods In this research, total RNA extracted from fetal hippocampal tissues was used to analyze miRNA and mRNA expression via Affymetrix miRNA 4.0 and PrimeView Human Gene Expression Array, respectively. Then miRNA and gene expression profiles were integrated by correlation analysis to identify dysregulated miRNAs with their predicted target mRNAs. Microarray data were further validated by real-time PCR. Regulation of zeste homolog 2 (EZH2) expression by hsa-miR-138 was determined by luciferase reporter assay. Results We analyzed microRNA expression profile in hippocampal tissues from DS fetal using miRNA microarray. Further with the use of mRNA microarray data, we integrate miRNA expression and mRNA expression in hippocampus of trisomy 21 fetus to elucidate the mechanism that underlying DS abnormalities. We characterized the repertoire of specific miRNAs involved in hippocampus in trisomy 21 patients, highlighting hsa-miR-138 and hsa-miR-409, in particular the importance of hsa-miR-138, especially the -5p strand. Furthermore, the expression level of predicted target genes of hsa-miR-138-5p in trisomy 21 fetus, including zeste homolog 2 (EZH2) were further confirmed. In addition, luciferase assay indicated that EZH2 was a direct target of hsa-miR-138 in HEK293T cells. Conclusion The function of hsa-miR-138-5p and its target EZH2 was involved in hippocampus in DS patients. Our findings provide a clue to study the underlying molecular mechanisms in DS patients, and its potential contribution in improving understanding of intellectual disability development in DS patients. Electronic supplementary material The online version of this article (doi:10.1186/s12929-016-0265-0) contains supplementary material, which is available to authorized users.

We recently observed an increased frequency of binucleated micronucleated lymphocytes in women who had a Down syndrome (DS) child before 35 years of age and the fluorescencein situhybridization analysis revealed that micronuclei were mainly originating from chromosomal malsegregation events, including chromosome 21 malsegregation. That study indicated that women who have a DS child at a young age might have a genetic predisposition to chromosome malsegregation in both somatic and germ line cells. Further studies from our group confirmed increased chromosome damage in blood cells of women who had a DS child at a young age and pointed to a possible role for polymorphisms in folate-metabolizing genes in affecting both chromosome damage and DS risk. In the present article, we review the most recent findings on mechanisms and risk factors for chromosome 21 nondisjunction that lead to DS. Multiple risk factors are likely involved in chromosome nondisjunction; they act at different times in the meiotic process and can be of genetic or environmental (epigenetic) origin. We also discuss the increased risk of developing Alzheimer's disease (AD) later in life that was observed in women who had a DS child at a young age. Studies performed in the last years that have shown that the brain is, in fact, a complex genetic mosaic of aneuploid and euploid cells support the unified hypothesis trying to relate DS, trisomy 21, and AD.