Why is it useful for diagnosing monosomies and trisomies

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 Trisomies and Monosomies. What are trisomies and monosomies? Your provider will collect cells from the placenta in one of two ways: either through your cervix with a thin tube called a catheter, or with a thin needle through your abdomen.

CVS is usually done between week 10 and 13 of pregnancy. For this test: You'll lie on your side or your stomach, depending on which bone will be used for testing. Most bone marrow tests are taken from the hip bone. The site will be cleaned with an antiseptic. You will get an injection of a numbing solution. Once the area is numb, the health care provider will take the sample.

For a bone marrow aspiration, which is usually performed first, the health care provider will insert a needle through the bone and pull out bone marrow fluid and cells. You may feel a sharp but brief pain when the needle is inserted. For a bone marrow biopsy, the health care provider will use a special tool that twists into the bone to take out a sample of bone marrow tissue. You may feel some pressure on the site while the sample is being taken.

Will I need to do anything to prepare for the test? You don't need any special preparation for karyotype testing. Are there any risks to the test? What do the results mean? Some disorders caused by chromosomal defects include: Down syndrome , a disorder that causes intellectual disabilities and developmental delays Edwards syndrome, a disorder that causes severe problems in the heart, lungs, and kidneys Turner syndrome , a disorder in girls that affects the development of female characteristics If you were tested because you have a certain type of cancer or blood disorder, your results can show whether or not your condition is caused by a chromosomal defect.

Is there anything else I need to know about a karyotype test? Washington D. Atlanta: American Cancer Society Inc. Amniocentesis; [updated Sep 2; cited Jun 22]; [about 2 screens]. Atlanta: U. C: American Association for Clinical Chemistry; c— Chromosome Analysis Karyotyping ; [updated Jun 22; cited Jun 22]; [about 2 screens]. Down Syndrome; [updated Feb 28; cited Jun 22]; [about 2 screens].

Mayo Foundation for Medical Education and Research; c— Bone marrow biopsy and aspiration: Overview; Jan 12 [cited Jun 22]; [about 4 screens]. Chronic myelogenous leukemia: Diagnosis and treatment; May 26 [cited Jun 22]; [about 5 screens]. Bone Marrow Examination; [cited Jun 22]; [about 2 screens]. Overview of Chromosome and Gene Disorders; [cited Jun 22]; [about 2 screens]. Bethesda MD : U. Department of Health and Human Services; What are the types of genetic tests?

Health Encyclopedia: Chromosome Analysis; [cited Jun 22]; [about 2 screens]. Alternatively, chromosomal gain may activate oncogenes [ 12 ].

UPD defined as two copies of a chromosomal pair originate from one single parent during meiosis, may also increase genomic instability by activating oncogenes or inactivating TSGs in MDS [ 13 ]. Complex karyotype often implies an increased risk of progressing to AML and unfavorable outcomes in MDS patients [ 15 ].

These chromosomal aberrations appear to be mechanisms to interpret disease progression. Additionally, environmental risk factors may also engender the pathogenesis of MDS. For instance, iron overload-induced oxidative stress may inhibit hematopoiesis by altering the supportive bone marrow stroma environment [ 5 ]. Thus, detection of chromosomal abnormalities may afford valuable information for accurate diagnosis of MDS, and may also optimize current therapeutic strategies for MDS patients.

The advent of these techniques has contributed to the investigation of chromosomal changes in MDS, including unbalanced chromosomal deletions and gains as well as balanced translocations [ 16 ]. The chromosomal findings will enhance our understanding of the pathogenesis of MDS.

In this review, we will not only recapitulate the current knowledge of common chromosomal aberrations in MDS, but also summarize the techniques for detecting chromosomal aberrations in MDS. Specifically, we will also introduce the application, advantages and limitations of each technique. Del 5q , trisomy 8, del 20q , del 7q , monosomy 7, and complex karyotypes are the commonest chromosomal aberrations in MDS [ 17 ]. Loss, gain, and UPD of genomic materials in these chromosomes are associated with the initiation and progression of MDS.

MDS patients with isolated del 5q often have a good prognosis, however, when accompanied with additional chromosomal aberrations, their prognosis becomes unfavorable [ 20 ]. The chromosome band 5q31 is the most frequently deleted region, including 2 different commonly deleted regions CDRs. The proximal 5q Haploinsufficiency of many candidate genes may potentially alter hematopoiesis, resulting in the phenotype of MDS patients with del 5q and malignant transformation [ 23 ].

For instance, RPS14 gene encodes a ribosomal protein small subunit 14 which influences the maturation of erythroid progenitor cells [ 24 , 25 ]. Haploinsufficiency of RPS14 gene may affect the p53 pathway, and the subsequent loss of p53 rescues erythropoiesis and contributes to clonal progression [ 26 ]. Pathogenetic mechanisms in del 5q MDS seem to involve hemizygous mutations in addition to haploinsufficiency, and may be modified by other somatic alterations influencing genes on other chromosomes [ 27 ].

Moreover, selection of particular treatment may rely on the presence of specific chromosomal aberrations. Low-risk, transfusion-dependent MDS patients with del 5q are reported to respond well to lenalidomide [ 28 — 30 ]. So accurate detection of del 5q is not only important for precise diagnosis of MDS, but also vital for individualized treatment of MDS patients.

Despite the association between particular chromosomal lesions and somatic mutations has not been clarified, several studies have reported that trisomy 8 was related to an IDH or ASXL1 mutation in MDS harboring trisomy 8 [ 36 , 37 ].

Complexity of chromosomal aberrations have a great impact on the overall survival OS of MDS patients. Clonal heterogeneity has been regarded as a specific cytogenetic characteristic of MDS. Usually, clonal evolution is a predictor for disease progression [ 3 ]. MDS patients with trisomy 8 and del 5q as independent clone had a remarkably longer time to progress to AML than those with clonal evolution [ 40 ]. Analysis of whole gene expression revealed that most genes on chromosome 8 are overexpressed in AML trisomy 8.

Hence the gene-dose effect may lead to leukemic progression of MDS with trisomy 8 [ 41 ]. Furthermore, MDS patients with trisomy 8 are more likely to respond to immunosuppressive agents than other subtypes of MDS [ 42 ]. Isolated del 20q has been found both in primary and therapy-related MDS patients.

Those patients often manifest anemia and thrombocytopenia, which involve bone marrow dysplasia [ 45 ]. Del 20q is considered to derive from a pluripotent stem cell and may exacerbate malignancy due to the deletion of tumor suppressor genes [ 46 ].

In the past several years, many studies have been initiated to detect the CDR on chromosome The CDR can be narrowed on chromosomal bands from 20q For example, the E2F1 gene on band 20q Increased levels and activity of E2F1 transcription factor have been observed in myelodysplastic bone marrow [ 48 , 49 ].

Isolated del 20q in MDS is a favorable recurrent chromosomal aberration, with higher reticulocyte counts, fewer bone marrow blasts, and an indolent clinical course [ 50 , 51 ]. The survival of patients with a del 20q was considered to be significantly longer than other MDS patients [ 52 ]. Thus, MDS patients with isolated del 20q usually have a relatively favorable prognosis.

However, as the size of chromosome 20 is too small, the traditional cytogenetic analysis is difficult to pinpoint chromosomal regions for its deletion [ 53 ]. So MDS with del 20q may be further stratified by additional cytogenetic and molecular techniques.

Deletion of chromosome 7q del 7q is also frequently found in MDS and are associated with a poor prognosis [ 54 ]. The percentage of del 7q cells is significantly higher in HSC and progenitor compartments than in lymphocytes of MDS patients [ 55 ].

Multiple investigations of MDS samples with interstitial del 7q have identified 3 potential CDRs at chromosome bands 7q22, 7q34, and 7q [ 55 ]. Specifically, deletion of 7q22 in bone marrow cells could contribute to hematopoietic abnormalities, such as vandalized lymphoid repopulating potential, myeloid output discrepancy, and a remarkable proliferation of HSC [ 56 ].

Del 7q may engender the haploinsufficiency of several critical genes implicated in hematological malignancies, subsuming MLL3, CUX1, and EZH2 [ 57 — 59 ], which are responsible for the leukemic progression of MDS [ 60 ].

These chromosomal abnormalities often portend clonal evolution and highlight the vital role of del 7q in the pathogenesis of MDS [ 61 ]. Monosomal karyotype MK is defined as the existence of a single autosomal monosomy related with at least one additional structural alteration in the same clone, or at least 2 autosomal monosomies [ 62 ].

Monosomy 7 is the most prevalent chromosomal abnormality of MDS in childhood, and often exists as the sole cytogenetically visible chromosomal aberration [ 63 , 64 ]. The monosomy 7 clone had a relative disadvantage in erythroid differentiation [ 65 ]. Monosomy 7 has been regarded as an independent predictor of survival in patients with higher-risk MDS.

The addition of MK as a binary variable could improve the predictive accuracy of current models to estimate the survival of patients with MDS [ 66 ]. For example, a recent study has retrospectively analyzed primary patients, in order to elucidate the prognostic significance of MK in Chinese MDS patients. They have found that MK was significantly related to elderly patients, higher bone marrow blasts and relatively unfavorable cytogenetics.

Another study has investigated if an MK is related to OS independent of the number of cytogenetic aberrations in a population-based MDS cohort. They have found that monosomy 7 was responsible for worse OS in the entire cohort median 6 vs 39 months , including those with a coexisting complex karyotypes 6 vs 17 months [ 68 ]. Isolated monosomy 7 or monosomy 7 plus one additional aberration is associated with a median survival of Consequently, early stem cell transplantation is recommended as soon as a monosomy 7 clone was detected [ 69 ].

Monosomy 7 is also the commonest chromosome abnormality in the course of evolution from MDS to AML in patients with different bone marrow failure syndromes and DNA repair deficiencies [ 70 ]. Complex karyotype CK was defined as the existence of at least three chromosomal alterations and was especially prevalent in secondary MDS [ 71 , 72 ]. Complex karyotypes and large number of chromosomal abnormalities may reflect an inherent chromosomal instability that contributes to disease progression.

A higher incidence of complex karyotypes represents more aggressive disease [ 73 ]. The pathogenic mechanisms leading to complex karyotypes in MDS still remain vague. UPD may contribute to genomic instability by activating oncogenes and inactivating tumor suppressor genes, facilitating the development and progression of complex chromosomal aberrations [ 74 ]. Moreover, complex karyotypes in MDS may arise from gradual acquisition of genetic changes in individual cells during clonal evolution or by extensive chromosome fragmentation and reorganization at a single event known as chromothripsis [ 75 ].

Patients with complex karyotypes often imply an unfavorable outcome, a shorter median OS, only 3 months, and propensity toward malignant progression. Multiple chromosomal aberrations often portend an adverse prognosis and difficult treatment [ 76 ]. Analysis of complex karyotypes facilitates the identification of latent unbalanced chromosomal alterations and candidate regions of genes responsible for the progression of MDS.

These regions can then be investigated further at the molecular level, which may render more accurate diagnosis of MDS and help to find potential targets for therapeutic interventions in the future. Cytogenetic findings are important for the diagnosis, prognosis evaluation and treatment selection of MDS patients [ 77 ]. Although these techniques are varying in depth, scope and cost, they are important for detecting diverse chromosomal abnormalities in MDS.

It can provide a whole chromosomal view of visible aberrations in chromosome number and structure simultaneously [ 80 ]. Furthermore, the simplicity of MC assay allows for the feasibility of discerning single cellular clones [ 81 ]. The chromosomal aberrations detected by MC often have strong prognostic value. These are the major advantages of MC. The resolution of conventional MC is quite low. This method also requires proliferating cells, and to a large extent, relies on specialist experience for discriminating meaningful data [ 84 ].

Most importantly, MC is unable to identify UPD because the chromosome banding patterns remain unaltered [ 86 ]. In some patients, MC may even fail to come up with informative results due to low resolution and non-dividing cells. Consequently, the technical limitations of MC may lead to underestimate of the extent of chromosomal abnormalities. FISH is also able to assess large numbers of interphase nuclei, so it can overcome some limitations of standard MC [ 87 ].

The diagnostic information from FISH is important for stratification of MDS into the appropriate subtypes and cytogenetic risk groups [ 88 ]. B D8Z2 probe reveals trisomy 8. Compared with conventional chromosome banding analysis, FISH has some remarkable advantages. First, FISH can be utilized for non-proliferating cells, a large amount of cells can be assessed with relatively less lab expenditure.

Third, FISH with a panel of probes can also be used to monitor disease progression and response to therapy, especially if it could be performed on peripheral blood samples [ 90 ].

Moreover, FISH can also putatively be applied to monitor lower-risk patients receiving supportive care only. The detection of cytogenetic aberrations can potentially facilitate early therapeutic interventions [ 91 ]. The major limitation of FISH is that it only detect particular structural or numerical chromosomal aberrations at specific locus, so those chromosomal abnormalities regarding other regions may be neglected [ 92 , 93 ]. When metaphase cells are fewer than 20, FISH is recommended to promote the accuracy for probing recurrent MDS-related chromosome aberrations [ 94 ].

Spectral karyotyping SKY is a novel technique for detecting chromosomal aberrations in myeloid malignancies. Based on the advancement of FISH, this technique has combined chromosome painting and multi-color fluorescence, enabling each of 23 chromosome pairs to be stained with a different color [ 95 ]. The advantage of SKY is that it can unravel chromosomes of unknown origin, and clarify if one of the parents is a carrier of a balanced structural abnormality.

SKY can also detect chromosomal rearrangements and minimal aberrations in MDS patients with complex karyotypes, displaying better pictures of karyotypes [ 96 ].

So SKY can overcome some defaults of the traditional banding methods, and reveal previously unrecognized chromosomal translocations. Furthermore, SKY is still crucial in detecting complex chromosomal abnormalities, so it also contributes to finding new MDS subgroups. In combination with other cytogenetic and molecular techniques, SKY may become a very powerful tool for the diagnosis, treatment and prognosis of MDS patients [ 97 ]. The resolution limit of SKY is roughly 1—2 Mb, similar to traditional chromosome banding techniques, so minor structural aberrations of less than one band cannot be visualized [ 98 ].

Therefore, SKY should combine with additional high-resolution techniques to pinpoint the site of chromosomal breakage in MDS. The rapid progress of high-resolution genome-wide single nucleotide polymorphism-array SNP-A technology is characterized by hybridization of sample DNA to probes specific for allelic variants in microarrays which can detect both CNV and UPD [ 99 ]. SNP-A can precisely pinpoint the location and size of submicroscopic chromosomal aberrations.

Moreover, high-resolution SNP-A has become one of the most powerful techniques to detect complex chromosomal lesions in myeloid malignancies. Approximately SNP-A has many advantages over conventional techniques. Those small cryptic chromosomal loss and gain can be identified by SNP-A.

However, there are still some limitations of SNP-A. The sensitivity of SNP-A still remains a relatively low level. Two factors should be considered when applying SNP-A as a clinical cytogenetic tool. Second, whether the chromosomal aberrations detected by SNP-A have any potential clinical significance [ ]. Hence combined application of SNP-A with traditional cytogenetic techniques may maximize the detection rate of chromosomal abnormalities in MDS.

This method utilized competitive hybridization of differentially labeled fragmented sample DNA and control DNA to the genome at the microarray platform to detect chromosomal aberrations [ ]. The fluorescence ratio of sample vs. Copy number alterations CNA of subtle chromosomal regions including potential candidate genes can be revealed [ ].