Why are some trisomies never observed

In trisomy 18 , there are three copies of chromosome 18 in every cell of the body, rather than the usual pair. The term "monosomy" is used to describe the absence of one member of a pair of chromosomes. Therefore, there are 45 chromosomes in each cell of the body instead of the usual Monosomy X, or Turner syndrome , occurs when a baby is born with only one X sex chromosome, rather than the usual pair either two Xs or one X and one Y sex chromosome. For Patients. Contact the Developmental Medicine Center Fax Down syndrome is also known as Trisomy 21, because the person has three copies of chromosome 21 instead of two.

There are three types of Down syndrome. In Mosaic Down syndrome, the extra chromosome spontaneously appears as the embryo develops. Translocation Down syndrome, which accounts for approximately five per cent of cases, is inheritable.

Some of the physical characteristics of Down syndrome may include:. All people with Down syndrome will experience some delay in their development and some level of learning disability. Learn more about Down syndrome. In Victoria, Edward syndrome affects about one in 1, pregnancies.

Edward syndrome is also known as Trisomy 18, because the person has three copies of chromosome 18 instead of two. Some of the characteristics of Edward syndrome may include:. In Victoria, Patau syndrome affects around one in 3, pregnancies. Patau syndrome is also known as Trisomy 13, because the person has three copies of chromosome 13 instead of two. Some of the characteristics of Patau syndrome may include:. Sometimes, signs of trisomy conditions may be evident during the pregnancy.

Some of these signs may include:. If your child has been diagnosed with a trisomy condition, it may be helpful to speak to a genetic counsellor. Genetic counsellors are health professionals qualified in both counselling and genetics. Genetic counsellors are trained to provide information and support that is sensitive to your family circumstances, culture and beliefs.

The Genetic Support Network of Victoria GSNV is connected with a wide range of support groups throughout Victoria and Australia and can connect you with other individuals and families affected by trisomy conditions. This page has been produced in consultation with and approved by:. During fetal development, the diaphragm or abdominal wall may fail to properly fuse, allowing the abdominal organs to protrude.

The characteristic features of Angelman syndrome are not always obvious at birth, but develop during childhood. ASD is a complex disorder that affects a person's ability to interact with the world around them.

The cause of birth defects is often unknown, speak to your GP if you are at increased risk of having a baby with a congenital anomaly. These genes are all within the region of interest [ 9 ]. ZNF69 has no mouse homolog. Our search of the DECIPHER database that reports chromosomal gains gene duplications and partial duplications as well as losses gene deletions and partial gene deletions revealed the following:.

Without exception, for all the epigenetic factors surveyed, we observed copy number variants in individuals who, although often clinically abnormal, survived gestation. However, in some cases, there were gains, but no losses, and in others, vice versa. None of the genes for epigenetic factors that we examined on chromosome 1 showed extensive sex specific differences in incidence of copy number variation Table 1.

Of the fifteen male variants, eight were duplications and four were deletions; there were no female duplications and the two females had heterozygous deletions. These observations led us to systematically explore the sex bias along chromosome 1 and 19 by plotting a marker of this bias, the posterior gain rate of selected individual genes, in serial order from short arm telomere pter to the long arm telomere qter using gains as the copy number variant for the screen See Methods and Fig 2A and 2B.

Our screen revealed regions involving three cytogenetic bands on chromosome 19, in which the sex ratio of gains was skewed 19p Systematic skewing of posterior gain rate M:F sex ratio on chromosome 19 A but not chromosome 1 B.

The grey box shows previous candidate regions, based on living females with partial trisomies. Note abnormal M:F posterior gain ratio in the candidate region of chromosome 19, but not on chromosome 1. Rarely, there was a female with a de novo duplication that because of its size, affected several genes in the region; such de novo variants may have arisen after X inactivation had occurred.

We also observed a second notable region on the long arm of chromosome Within 41 and Of note, both domains are within the candidate region reported by Migeon et al, , [ 9 ] Fig 2B , grey boxes.

Posterior rate M:F sex ratio of duplications, deletions and total variants on chromosome 19, at kb intervals throughout the p A and q B arms of the chromosome from pter to qter.

Note the excess of males for both total variants and duplications in the domain 4. Not all of the zinc finger genes on the long arm are shown, as their patterns are not remarkable. Also shown are the locations of some candidate genes in italics with respect to zinc finger clusters. To estimate the significance of the observed sex differences in duplications on chromosome 19, we used a permutation test.

We distributed the observed total duplications on chromosome 19 randomly by sex and at random positions in KB bins of that chromosome. In the actual data, the highlighted 8MB region from bin 4. Thus, the simulations directly show that the significance of a ratio of 4.

We can estimate how many more simulations would be required to observe a ratio of 4. The tail of this distribution is approximately power law with exponent m -9 , where m is the maximum average ratio, so we estimate that the simulations would have to be run 10 4 or 10 5 times longer to observe an average posterior sex ratio greater than the observed value of 4. We looked for sex differences on all the other human autosomes using total gains duplications and partial duplications as the determinant for this screen Figs A-T in S1 Fig.

Although the total gains in some genes originated more from males than females i. No sector showed the extensive domain of skewing, observed on the short arm of chromosome The exceptional regions on chromosome 7 and 12 were assayed again, this time, with respect to duplications; we found that in every case they were limited to relatively few genes—unlike that seen for the chromosome 19 short arm. In addition, our previous studies showed that full trisomies 7 and 12 have a single active X [ 12 ].

We suggest that regions with skewed sex ratios on other chromosomes merit future study to determine the reason for the more localized sex differences. On chromosome 19 there are several dense clusters of zinc finger proteins that differ with respect to sex ratio of variants and female loss i. These dense clusters of zinc finger proteins are known to be unique to chromosome 19 [ 22 ] and our survey of several other chromosomes attest to their uniqueness on chromosome They are thought to be repressors of endogenous retroviruses ERV [ 22 ], which have been implicated in providing novel transcription factor binding sites, and generating novel functional lncRNAs [ 23 ].

One of the dense clusters is in the middle of 19p Our observations indicate the need to further investigate the role of the chromosome 19p Table 2 shows the candidate genes located within the 4.

There are also unknown open reading frames, as well as many genes that are unlikely to be related to X inactivation, including those for the LDL receptor and TGFB1. Except for zinc finger genes and unknown open reading frames, we could not identify obvious candidates among the 22 genes in the 41— Most of the genes within this region approximately show marked skewing from the expected 50 sex ratio of duplications, reflecting paucity of females.

The region includes ordinary protein coding genes as well as epigenetic factors—not unexpected because of the large size of some de novo amplifications. This also impedes the effort to precisely map the limits of the critical regions. As sex differences in the incidence of duplications and deletions are not expected, we interpret the skewing to be the result of selective embryonic loss. Female embryos are systematically lost prior to implantation if they duplicate the relevant chromosome 19 genes.

Our observations were exactly as we predicted: We expected that a female with partial trisomy of a gene or genes on either chromosome 1 or 19 might end up with two active X chromosomes, and that this would lead to her demise in utero. Conceivably, females with duplications of our candidate region on chromosome 19 are being lost for reasons unrelated to X inactivation; however, in light of our previous studies that implicate chromosome 19, and in absence of similar regions on the other chromosomes, other interpretations of our results seem unlikely.

Of all human chromosomes, chromosome 19 has the highest density of genes, more than double the genome average [ 25 ]. Nearly one-quarter of them belong to tandem-arrayed families. Clearly, most of the genes in our regions of interest are passengers, whereas the drivers have not yet been definitively identified.

Table 2 shows some of the more likely driver candidates, as they could repress XIST. Although primarily functioning as a maintenance DNA methyltransferase, DNMT1 or its splice variant is thought to have a de novo methylation function for imprinted genes, including Xist [ 27 , 28 ].

All of these factors are functioning in the early mammalian embryo, prior to gastrulation, when random X inactivation occurs [ 27 — 30 ]. Direct testing of candidate genes is impeded by bans on human embryo studies, and the fact that the human embryonic stem cells currently available have already undergone X inactivation. Nonetheless, our observations should stimulate the development of a suitable human assay system. Our model of an autosomal XIST repressor calls for only one dosage sensitive gene.

Other drivers may well be dosage insensitive. It is difficult to know how such a dosage sensitive repressor functions, because in normal diploid cells there are two copies of the relevant autosomal repressor and only a single XIST locus to silence.

It is unlikely that the product of both chromosome 19 genes is needed as deletion of one locus seems to be tolerated, so that the right dosage may require some form of competitive inhibition.

Alternatively, physical contact with a single chromosome 19 may be needed to assure that only one XIST gene is repressed. There are significant differences in the process of X inactivation among mammals including its timing, presence of parental imprinting and nature of the long non-coding RNAs; such differences are attributable to evolutionary changes within the X inactivation center and the staging of embryogenesis [ 31 ]. The clusters of zinc finger genes arose on chromosome 19 after the split of humans from rodents, and reside on chromosome 19 in other primates [ 22 ].

In addition, the major region of skewing—on the human chromosome 19 short arm—is found on two different chromosomes in rodents mouse chromosomes 17 and 9, and rat chromosomes 9 and 8 , and the long arm region is found on yet another chromosome. Percec et al. They identified regions of mouse chromosomes 5, 10 and 15 that seemed to affect choice of inactive X; none of these chromosomes is orthologous to human chromosome Further identification of the relevant genes will tell us if we share mechanisms with other mammals, or if such species differences reflect the lack of shared strategies to create a single active X.

Selective loss of females at the time of X inactivation could help explain why the human male: female ratio at birth is 1. The exact number differs with country and is influenced by the recent advent of sex selection by prenatal diagnosis; Yet, without doubt more males are born than females throughout the world. The reason for the skewed sex ratio has been enigmatic in absence of bias in gametogenesis or fertilization in favor of Y-bearing sperm, and in light of evidence that more males are lost than females at every stage post-implantation [ 34 , 35 ].

As X activation is a dosage sensitive process, it is more hazardous for females than for males; males have only a single X to maintain, but females face the danger of activating more than one X chromosome inactivating more than one XIST locus , which would be lethal. It seems that females, who by chance, inherit a duplication of their dosage sensitive XIST repressor s cannot survive. The lack of females with partial trisomies of our candidate region on chromosome 19 affirms their selective preimplantation loss.

Such a loss of females must contribute to the distorted sex ratio at birth. Just as the absence of autosomal monosomies from studies of fetal wastage tell us which zygotes have been lost, the absence of females with partial trisomies of the region 4. Not only does the sex ratio of copy number variants tell us about fetal loss, but it can also provide insights into disease processes.

For many genetic diseases of autosomal origin, including autism and Hirschsprung disease, there is a marked sex difference in the expression of the disease, not apparently attributable to hormones or X-linked genes.

We suggest that sex differences in some copy number variants, and not others, may provide useful clues to mechanisms underlying the deviations from expected sex ratios for the risk of disease. Our data draw attention to the potentially significant role played by autosomal copy number variation in establishing the active X, and in mediating gender bias in disease manifestations; therefore they warrant further investigation.

Such potential candidates for XIST repressors included epigenetic factors, histone structural components, histone methyltransferases, DNA methyltransferases, zinc finger proteins, heteronuclear proteins, long non-coding RNAs, other genes implicated in X inactivation and genomic imprinting and undefined open reading frames. Detailed analysis of chromosome 19 was carried out by KB bins from pter to qter, using M: F sex ratios for total copy number variants, duplications and deletions, which were plotted for Fig 3 , as described below.

To systematically sample a sizable fraction of human genes on all the autosomes, we used the available DECIPHER gene list, a compilation of genes with open-access patient sequence variants, or DDD research sequence variants. On September 6 th , this list contained genes, of which were protein coding.