The phenotype of persons having mosaicism for trisomy 21/Down syndrome reflects the percentage of trisomic cells present in different tissues

Papavassiliou, Paulie; York, Timothy P.; Gursoy, Nurcan; Hill, Gloria; Nicely, Lauren Vanner; Sundaram, Usha; McClain, Allison; Aggen, Steven H.; Eaves, Lindon J.; Riley, Brien P.; Jackson‐Cook, Colleen

doi:10.1002/ajmg.a.32729

Cited by 95 publications

(93 citation statements)

References 19 publications

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“…In addition, we cannot exclude the possibility of karyotype mosaicism in some of the plants, i.e., that not all cells of the individuals carry the same chromosome number. This type of situation is thought to be responsible for some of the phenotypic variation observed in aneuploid syndromes in humans (Papavassiliou et al 2009), but it is unclear whether such mosaicism exists in plants. In our populations of aneuploid individuals, we did not observe any phenotype that could be identified as a clear example of cellular mosaicism.…”

Section: Resultsmentioning

confidence: 99%

Phenotypic Consequences of Aneuploidy inArabidopsis thaliana

et al. 2010

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Aneuploid cells are characterized by incomplete chromosome sets. The resulting imbalance in gene dosage has phenotypic consequences that are specific to each karyotype. Even in the case of Down syndrome, the most viable and studied form of human aneuploidy, the mechanisms underlying the connected phenotypes remain mostly unclear. Because of their tolerance to aneuploidy, plants provide a powerful system for a genome-wide investigation of aneuploid syndromes, an approach that is not feasible in animal systems. Indeed, in many plant species, populations of aneuploid individuals can be easily obtained from triploid individuals. We phenotyped a population of Arabidopsis thaliana aneuploid individuals containing 25 different karyotypes. Even in this highly heterogeneous population, we demonstrate that certain traits are strongly associated with the dosage of specific chromosome types and that chromosomal effects can be additive. Further, we identified subtle developmental phenotypes expressed in the diploid progeny of aneuploid parent(s) but not in euploid controls from diploid lineages. These results indicate long-term phenotypic consequences of aneuploidy that can persist after chromosomal balance has been restored. We verified the diploid nature of these individuals by wholegenome sequencing and discuss the possibility that trans-generational phenotypic effects stem from epigenetic modifications passed from aneuploid parents to their diploid progeny.

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Section: Resultsmentioning

confidence: 99%

Phenotypic Consequences of Aneuploidy inArabidopsis thaliana

et al. 2010

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“…As might be expected, the severity of the clinical picture in such DS cases is related to the degree of T21 mosaicism, usually ascertained by examination of in vitro cultured blood lymphocytes and, more rarely, uncultured tissue samples, such as buccal smears [Papavassiliou et al, 2009;Shin et al, 2010].…”

Section: High-grade T21 Mosaicism In Ds Casesmentioning

confidence: 86%

Trisomy 21 Mosaicism: We May All Have a Touch of Down Syndrome

Hultén

Jonasson

Iwarsson

et al. 2013

Cytogenet Genome Res

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Ever increasing sophistication in the application of new analytical technology has revealed that our genomes are much more fluid than was contemplated only a few years ago. More specifically, this concerns interindividual variation in copy number (CNV) of structural chromosome aberrations, i.e. microdeletions and microduplications. It is important to recognize that in this context, we still lack basic knowledge on the impact of the CNV in normal cells from individual tissues, including that of whole chromosomes (aneuploidy). Here, we highlight this challenge by the example of the very first chromosome aberration identified in the human genome, i.e. an extra chromosome 21 (trisomy 21, T21), which is causative of Down syndrome (DS). We consider it likely that most, if not all, of us are T21 mosaics, i.e. everyone carries some cells with an extra chromosome 21, in some tissues. In other words, we may all have a touch of DS. We further propose that the occurrence of such tissue-specific T21 mosaicism may have important ramifications for the understanding of the pathogenesis, prognosis and treatment of medical problems shared between people with DS and those in the general non-DS population.

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“…[3][4][5] Compared to constitutional defects in the same regions, mosaic abnormalities can result in milder phenotypes, as observed for neurofibromatosis type 1 (MIM 162200) and trisomy 21 (MIM 190685); interestingly, these same mutations have been observed in apparently healthy individuals. [6][7][8] A spectrum of clinical phenotypes, including Maffucci syndrome (MIM 614569), 9,10 McCuneAlbright syndrome (MIM 174800), 11 nevus sebaceus (MIM 162900), 12 Ollier disease (MIM 166000), 9,10 Proteus syndrome (MIM 176920), 13 and mosaic RASopathies, 14 have been associated with mosaicism.…”

mentioning

confidence: 99%

Characterization of Large Structural Genetic Mosaicism in Human Autosomes

Machiela¹,

Zhou²,

Sampson³

et al. 2015

The American Journal of Human Genetics

106

111

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Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

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The phenotype of persons having mosaicism for trisomy 21/Down syndrome reflects the percentage of trisomic cells present in different tissues

Cited by 95 publications

References 19 publications

Phenotypic Consequences of Aneuploidy inArabidopsis thaliana

Phenotypic Consequences of Aneuploidy inArabidopsis thaliana

Trisomy 21 Mosaicism: We May All Have a Touch of Down Syndrome

Characterization of Large Structural Genetic Mosaicism in Human Autosomes

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