Single-Cell Transcriptomics of Cultured Amniotic Fluid Cells Reveals Complex Gene Expression Alterations in Human Fetuses With Trisomy 18

Abstract

Trisomy 18, commonly known as Edwards syndrome, is the second most common autosomal trisomy among live born neonates. Multiple tissues including cardiac, abdominal, and nervous systems are affected by an extra chromosome 18. To delineate the complexity of anomalies of trisomy 18, we analyzed cultured amniotic fluid cells from two euploid and three trisomy 18 samples using single-cell transcriptomics. We identified 6 cell groups, which function in development of major tissues such as kidney, vasculature and smooth muscle, and display significant alterations in gene expression as detected by single-cell RNA-sequencing. Moreover, we demonstrated significant gene expression changes in previously proposed trisomy 18 critical regions, and identified three new regions such as 18p11.32, 18q11 and 18q21.32, which are likely associated with trisomy 18 phenotypes. Our results indicate complexity of trisomy 18 at the gene expression level and reveal genetic reasoning of diverse phenotypes in trisomy 18 patients.

Trisomies Reorganize Human 3D Genome

“…Indeed, autosomal aneuploidies including the presence of multiple copies of one chromosome or an entire set of chromosomes are easily tolerated by cells in culture while are typically hazardous or fatal for the organism. One reason (though probably not the only one) for that is pan-genomic transcriptional dysregulation, which is observed in all trisomies [31][32][33]. In this regard, an extra chromosome should be considered not as just an inert DNA mass localized somewhere inside the nucleus, or as just a source of additional copies of genes, but as a "bull in a China shop", whose presence disturbs some fine-tuned structural and functional relationships between (and within) chromosomes.…”

Prenatal diagnosis and genetic counseling of a paternally inherited microduplication 18q11.1 to 18q11.2 in a chinese family

“…Still it is interesting and needs further investigations that the in the reported family duplication region in 18q11.1q11.2 encompasses 25 genes as ROCK1, GREB1L, ABHD3, ANKRD29, AQP4, CABLES1, CABRY, CHST9, CTAGE1, ESCO1, GATA6, IMPACT, KCTD1, LAMA3, MIB1, NPC1, OSBPL1A, PBBP8, RIOK3, RP11, SNRPD1, SS18, TAF4B, TMEM241 and TTC39C. In these 25 genes, genetic alterations of ROCK1, ABHD3, ANKRD29, CABLES1 and CTAGE1, including deletion, methylation, and point mutations, are directly involved in the development of human cancer and other diseases [11][12][13].…”