Which disorder is characterized by an abnormal number of autosomes

Down syndrome is very well-known trisomy. Trisomy was first described in by scientist John Down, and later elaborated upon with much greater detail through the Karyotype of Trisomy discovery in There are three types of origin. Mosaic means that person has some cells with trisomy and some without. The last two examples have less severe symptoms. The extra chromosome is much worse.

People with Down syndrome have typical physical appearance. They have also motor problems because of small muscle tone. Carriers suffer more from leukemias , infections, cardiac malformations, epilepsy , hypothyroidism and Alzheimer disease.

The IQ of people with Down syndrome is about It means that they reach a level of a small child — about 6 years old. On the second side their character is very friendly, warm and loving. Such rearrangements include inversions, which are caused by a two-break event and the end-to-end reversal of the intervening chromosomal segment; translocations, which result from the exchange of chromosome segments between two or more chromosomes; and insertions, which occur when a segment of one chromosome is translocated and inserted into a new region of the same chromosome, the other homolog, or a nonhomologous chromosome.

These rearrangements may be pathogenic if a gene s is disrupted by a rearrangement breakpoint, a novel fusion gene product is formed, or a position effect is exerted on genes neighboring the rearrangement. Compared with, for example, single-gene mutations, chromosome abnormalities often disrupt large numbers of developmentally important genes. Such imbalances may alter the dosage of genes expressed within the affected chromosomal segment, resulting in clinical consequences for the individual see Table 1.

Some imbalances result in a contiguous gene syndrome, in which multiple genes within the deleted or duplicated region are affected, each contributing a discrete clinical feature to the phenotype. For most deletion syndromes, deletion causes haploinsufficiency of a gene or genes in the region, in which the remaining intact copy of the gene does not produce sufficient gene product for normal function. Each chromosome can be divided into bands, which are sections of a chromosome that can be distinguishable from adjacent sections by lighter or darker variations in intensity following one or more staining methods.

The original reports of chromosome rearrangements were made prior to the development of these staining techniques. Thus, any rearrangements recognized under the microscope were either numeric or an altered segment of the chromosome large enough so that the affected homolog could be easily distinguished from the normal homolog based on the overall size of the chromosome.

The use of molecular cytogenetic technologies, such as fluorescence in situ hybridization FISH and microarrays, has allowed for the identification of cryptic or submicroscopic imbalances, which are not visible under the light microscope Figure 1. Numerous previously unrecognized microdeletion and microduplication syndromes have been identified by these molecular cytogenetic techniques. Probes are ordered on the x axis according to physical mapping positions, with the most proximal chromosome 15 q-arm clones on the left and the most distal chromosome 15 q-arm clones on the right.

In , Schmickel 3 first described contiguous gene syndromes CGS as involvement of multiple genes located in close proximity to each other on a chromosome. This term has been refined over the years and expanded to include a group of disorders defined by a deletion or duplication of a chromosomal segment spanning more than one disease gene, each affecting the phenotype independently.

CGS have been described for many disorders mapping to various chromosomes. Disorders now recognized as CGS often have subtle cytogenetic changes that cannot always be resolved with conventional cytogenetic methods. Of all cytogenetically visible structural abnormalities, the majority occur in the distal telomeric bands of the chromosomes. Several clinically well recognized genetic disorders are associated with terminal deletions, including deletion of distal 5p associated with cri du chat syndrome 4 and distal deletion of 4p associated with Wolf—Hirschhorn syndrome.

The development of sets of FISH probes for the simultaneous interrogation of all the unique human subtelomeres 29 , 31 , 32 has allowed for the detection of submicroscopic chromosomal abnormalities in patients with idiopathic mental retardation but without features suggestive of a particular syndrome. The largest study of subtelomeric abnormalities to date examined 11, cases with subtelomere FISH and detected pathogenic abnormalities in 2. Because the distal G-negative bands of the unique chromosome arms are gene-rich, 25 deletion or retention of this region may have profound clinical consequences in individuals with telomeric imbalances.

Thus, accurate delineation of the nature of the imbalance, either terminal or interstitial, is crucial for diagnosis and prognosis. Recent large-scale prospective studies using microarrays show interstitial deletions are two to three times more frequent than terminal imbalances.

Of these cases, 42 had interstitial deletions. In addition, six 3. The identification of complex rearrangements suggests chromosome abnormalities are often more complex than what was once thought.

Many recurrent chromosomal abnormalities are caused by nonallelic homologous recombination NAHR mediated by flanking segmental duplications.

Almost invariably, the abnormalities identified in individuals with the same genomic disorder are of identical size. For example, the common deletion in 7q For example, some of the rarer rearrangements of 17p Nonallelic homologous recombination predicts that reciprocal duplications of low copy repeat-mediated deletions should occur with equal frequency. The clinical significance of some of these reciprocal duplications is not known. For example, only two individuals had de novo microduplications of 3q29, whereas the remaining cases were inherited from a carrier parent.

Thus, the clinical significance of these duplications is unclear, and any phenotype may be modulated by an as yet unidentified genetic modifier. Several new syndromes, including 8p23 duplication 75 and 16p The study of 16p Recurrent microdeletions of 16p Carrier parents for the 16p The presence of varying degrees of learning disability in the adult family members suggests that some transmitted abnormalities are pathologic and have an underappreciated contribution to the phenotype.

For example, varying-sized deletions at Xp21 comprise a contiguous gene syndrome that encompasses seven disorders, ie, adrenal hypoplasia congenita, glycerol kinase, Duchenne muscular dystrophy, McLeod phenotype, chronic granulomatous disease, retinitis pigmentosa, and ornithine transcarbamylase deficiency.

The first recognized patient with an Xp21 contiguous gene deletion was diagnosed with Duchenne muscular dystrophy associated with chronic granulomatous disease, retinitis pigmentosa, and McLeod phenotype. Such an approach also allowed researchers to delineate the critical regions of trichorhinophalangeal syndrome type 1 and trichorhinophalangeal syndrome type 2, also known as Langer-Giedion syndrome.

Langer—Giedion syndrome combines the features of trichorhinophalangeal syndrome type 1 and multiple exostoses type 1. The cytogenetic basis of Langer—Giedion syndrome was unknown until high-resolution banding identified interstitial deletions in the long arm of chromosome 8 in patients with this syndrome, 82 , 83 and the location of the deletion was subsequently determined to be 8q Buhler et al 88 concluded that the Langer—Giedion syndrome is due to a deletion extending from 8q Thus, it was determined that Langer—Giedion syndrome, which combines features of trichorhinophalangeal syndrome Type 1 and multiple exostoses, is a contiguous gene syndrome caused by haploinsufficiency of both TRPS1 and EXT1.

Many of the recently identified syndromes have been identified through a genotype-first approach, rather than a typical phenotype-first approach. This approach took many years to observe several rare individuals and develop a syndrome. The resulting syndromes had very consistent phenotypes among patients. In contrast, the genotype-first approach identifies patients with the same or overlapping genomic alterations and then describes the phenotypes observed.

In this latter approach, the patients often display varying features, and in hindsight would not have been grouped based on clinical presentation alone.

Recurrent microdeletions of chromosome 10q In all cases, the majority of patients identified met the classical definition of a recurrent genomic disorder. The deletions were flanked by segmental duplications, the deletions were always apparently de novo in origin, and the patients had similar clinical features.

The genotype-first approach may also enable the identification of small deletions or duplications that reveal the causative genes for specific clinical features, which can aid diagnosis and prognosis. For example, researchers recently identified what is likely to be the causative gene for features of 2q32q33 microdeletion syndrome. Although deletions of varying sizes have been reported, the smallest region deleted in all patients contains at least seven genes.

Deletion of SATB2 has been suggested to cause the cleft or high palate of individuals with 2q32q33 microdeletion syndrome. The recent study identified three individuals with small deletions of this region, all of which spanned part of SATB2. Common clinical features among these individuals included severe developmental delay, behavioral problems, and tooth abnormalities.

Interestingly, only one of the individuals had a cleft palate. Because the individuals had a portion of only one gene missing and the presence of many of the features associated with the larger microdeletion syndrome, the study authors suggested deletion of SATB2 was sufficient to cause several of the clinical features associated with 2q32q33 microdeletion syndrome.

Chromosomal disorders are the most frequent cause of mental retardation and developmental disabilities in our population. The phenotypes are often complex, and the result of a gain or loss of multiple, dosage-sensitive genes in the altered segments.

The characterization of these complex phenotypes with overlapping deletions has allowed for the identification of genes causing particular features of the syndrome. The use of high-resolution technologies, such as microarrays, has allowed for the identification of new syndromes through a genotype-first approach at an unprecedented frequency never before imagined through the light microscope.

National Center for Biotechnology Information , U. Journal List Appl Clin Genet v. Appl Clin Genet. Published online Dec Aaron Theisen and Lisa G Shaffer. Author information Copyright and License information Disclaimer.

This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. This article has been cited by other articles in PMC. Abstract Many human genetic disorders result from unbalanced chromosome abnormalities, in which there is a net gain or loss of genetic material.

Keywords: chromosome, deletion, duplication, telomere, segmental duplication. Open in a separate window. Figure 1. Terminal rearrangements Of all cytogenetically visible structural abnormalities, the majority occur in the distal telomeric bands of the chromosomes. Recurrent abnormalities mediated by underlying genomic architecture Many recurrent chromosomal abnormalities are caused by nonallelic homologous recombination NAHR mediated by flanking segmental duplications.

Deletions of varying size may elucidate causative genes for syndromes Because many chromosomal alterations are large and encompass numerous genes, the ascertainment of individuals with overlapping deletions and varying clinical features may allow researchers to narrow the region in which to search for candidate genes.

Genotype-first approach to diagnosis Many of the recently identified syndromes have been identified through a genotype-first approach, rather than a typical phenotype-first approach. Summary Chromosomal disorders are the most frequent cause of mental retardation and developmental disabilities in our population. References 1.

Molecular mechanisms for constitutional chromosomal rearrangements in humans. Annu Rev Genet. A cytogenetic study of spontaneous abortions. Ann Hum Genet. Schmickel RD. Contiguous gene syndromes: a component of recognizable syndromes. J Pediatr. Partial deletion of the short arm of chromosome 5. Individualization of a new morbid state. Sem Hop Paris. Deficiency on the short arms of a chromosome No.

The discovery of microdeletion syndromes in the post-genomic era: review of the methodology and characterization of a new 1q41q42 microdeletion syndrome. Genet Med. Monosomy 1p36 deletion syndrome. Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome.

Am J Hum Genet. Monosomy 1p J Med Genet. A new chromosome 17q Nat Genet. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Microdeletion encompassing MAPT at chromosome 17q A further case of the recurrent 15q24 microdeletion syndrome, detected by array CGH.

These consist of 2 chromosomes that determine what sex they are X and Y chromosomes , and 22 pairs of nonsex autosomal chromosomes. Males are "46,XY" and females are "46,XX. Each chromosome contains sections of DNA called genes.

The genes carry the information needed by your body to make certain proteins. Each pair of autosomal chromosomes contains one chromosome from the mother and one from the father. Each chromosome in a pair carries basically the same information; that is, each chromosome pair has the same genes. Sometimes there are slight variations of these genes. The genes that have these variations are called alleles.

Some of these variations can result in a gene that is abnormal. An abnormal gene may lead to an abnormal protein or an abnormal amount of a normal protein. In a pair of autosomal chromosomes, there are two copies of each gene, one from each parent. If one of these genes is abnormal, the other one may make enough protein so that no disease develops.

When this happens, the abnormal gene is called recessive. Recessive genes are said to be inherited in either an autosomal recessive or X-linked pattern.

If two copies of the abnormal gene are present, disease may develop. However, if only one abnormal gene is needed to produce a disease, it leads to a dominant hereditary disorder. In the case of a dominant disorder, if one abnormal gene is inherited from the mother or father, the child will likely show the disease. A person with one abnormal gene is called heterozygous for that gene. If a child receives an abnormal recessive disease gene from both parents, the child will show the disease and will be homozygous or compound heterozygous for that gene.

Almost all diseases have a genetic component. However, the importance of that component varies. Disorders in which genes play an important role genetic diseases can be classified as:. Nature Reviews Genetics 2, All rights reserved. Figure Detail. Humans are much more able to tolerate extra sex chromosomes than extra autosomes. Klinefelter's males have a total chromosome number of 47, which includes two X chromosomes and one Y chromosome. According to convention, these males are designated as 47,XXY individuals.

Compared to autosomal trisomies, these sorts of sex chromosome trisomies are fairly benign. Affected individuals generally show reduced sexual development and fertility, but they often have normal life spans, and many of their symptoms can be treated by hormone supplementation.

The ability of humans to tolerate supernumerary sex chromosomes is quite remarkable, as individuals can survive with as many as four sex chromosomes. This tolerance most likely relates to both X inactivation and to the small number of genes on the Y chromosome. In fact, when cells from individuals with more than one copy of the X chromosome are analyzed under a microscope, all but one of the X chromosomes appear as condensed Barr bodies, the cytological manifestations of X-chromosome inactivation.

Supernumerary copies of the Y chromosome may be tolerated because the few gene products of the Y chromosome are not required for survival.

Figure 3 Monosomies are the opposite of trisomies, in that affected individuals are missing one chromosome, reducing their total chromosome number to Cells seem to be particularly sensitive to the loss of a chromosome, because the only viable human monosomy involves the X chromosome.

Females with a single copy of the X chromosome have the condition known as Turner's syndrome. Interestingly, the frequency of Turner's syndrome is significantly lower than that of sex chromosome trisomies, suggesting that a single X chromosome is insufficient for optimum cell function. The viable Turner's 45,X females display a wide range of symptoms, which include infertility and impaired sexual development, and these individuals are usually mosaics.

Table 1 Figure Detail It is difficult to estimate the true frequency of human aneuploidies, because the most seriously affected embryos probably do not survive to the developmental stage at which they can be scored, and many pregnancies may terminate before they are diagnosed. Nonetheless, rough rates of aneuploidy can be calculated by analyzing chromosomes in gametes and preimplantation embryos, and then making corrections for undetected chromosome compositions that could be lethal.

Figure 6 With the advent of DNA microarray technology, investigators are now able to measure the effects of trisomy 21 on the simultaneous expression of thousands of genes from multiple chromosomes. Using microarrays, several studies have documented widespread upregulation of chromosome 21 gene expression in brain samples obtained from aborted Down syndrome fetuses, compared to brain samples from unaffected fetuses of the same developmental age Mao et al.

In the data shown in Figure 5, a Z score is used to provide a rough estimate of the difference in gene expression between DS samples and normal samples. Z scores are not simply ratios of expression levels in DS and normal tissues.

The Z scores are plotted for multiple genes along the length of chromosome The positions of the genes involved in hereditary forms of Alzheimer's disease APP and amyotrophic lateral sclerosis SOD1 , superoxide dismutase are also indicated. Colored symbols in the plot represent four different fetal DS brain samples and four astrocyte cell lines obtained from DS brain samples.

The results show that the expression of many genes along the entire length of chromosome 21 is increased in DS. The increases observed for APP and SOD1 transcription are fairly typical of many genes, suggesting that their overexpression is not the major cause of DS symptoms. Importantly, control experiments Figure 6 comparing two normal brain samples showed much lower levels of variation, indicating that the changes in gene expression observed in DS fetal brain samples were not due to random fluctuations associated with the microarray technique.

Overall, the microarray results paint a complex picture of the molecular events that underlie DS. An ongoing challenge for DS research is to sort through the complex set of transcriptional changes associated with DS to identify those genes whose expression is most closely linked to DS phenotypes.

To this end, investigators have already constructed mouse models of chromosome 21 overexpression that reproduce some of the symptoms of DS Antonarakis et al. Researchers hope that these kinds of models will provide useful experimental systems for developing therapeutic interventions for this debilitating condition, which affects millions of people around the world. Antonarakis, S. Chromosome 21 and Down syndrome: From genomics to pathophysiology.

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