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International Risks Significant Diagnostic Errors #56 Focus Constitutional cyto- and molecular genetics: Karyotyping, FISH and CGH array Cytogenetics is the study of genetic material chromosomes are photographed and at the cellular level; molecular genetics studies rearranged into pairs for examination (a the structure and function of genes at a karyogram). molecular level (DNA). The various techniques The benefits of karyotyping are: used vary in their clinical application. This 1. It can view the entire genome. article is a brief summary of the indications for the most commonly-used techniques. It 2. It can visualize individual cells and is vital that the correct technique is used for individual chromosomes. a given clinical presentation or suspected The limits of karyotyping are: condition, as to use the incorrect technique 1. Resolution limited to around 5 Mb. International risks significant diagnostic errors. 2. An actively growing source of cells is Karyotyping required. It is important to note that classic karyotyping With this technique, lymphocytes from is timeconsuming, with the preparation of peripheral blood are cultured, using cells for examination taking several days. mitogens to stimulate the transformation In addition, live lymphocytes are required of the lymphocytes into mitotically active so blood samples need to arrive at the cells. The timing of harvesting of the cells is laboratory within a maximum of 48 hours engineered such that a maximum number after sampling, preferably sooner, to avoid of cells are in metaphase. The cells are failure of cell growth in culture. then fixed, and spread onto a slide. The chromosomes are stained using a number of stains, usually Giemsa (G-banding and Rbanding), which produces banding patterns on the chromosomes with a band resolution of 400 – 650 bands per haploid chromosome set. The chromosomes with their bands are then examined microscopically for abnormalities such April 2016 – as loss or gain of entire chromosomes, translocations of all or part of an arm of one -INTGB chromosome to another, or more subtle Fig. 1: A normal human karyogram (both male changes in banding patterns associated and female shown, which would of course not Focus 56 with various genetic syndromes. The appear in practice). 1/5 Limits of FISH: 1. One can see only the region of the genome complementary to the probe used. Fig. 2: Karyogram of a female patient with Trisomy 21. Fluorescence in situ hybridisation (FISH) Conventional karyotyping is limited to the detection of rearrangements involving more than 5 Mb of DNA. The resolution Fig.3: FISH on a metaphase from a Di George carrier. The green probe identifies the two of the FISH technique, using fluorescent chromosomes 22 (standard probe). The red probes, is about 100kb-1Mb in size. This probe is specific to the critical Di George region technique involves the hybridisation and is present on only 1 of the chromosomes 22, of fluorescently labelled specific DNA indicating a deletion on the other chromosome. sequence probes with patient DNA, and the subsequent microscopic detection of Array comparative genomic the presence, absence, abnormal copy number or pathological location of a given hybridisation: array CGH and fluorescence signal. The availability of SNP array specific locus probes for many known Array CGH compares the patient’s genome genetic defects has greatly increased the against a reference genome (normal control accuracy of detection of microdeletion and or standard) and identifies differences duplication syndromes. This very specificity between the two genomes and hence of the probes is however the main limitation locates regions of genomic imbalance of FISH: it can detect only the specific DNA (copy number variations (CNVs) in the sequences to which it is complimentary patient. A CNV is defined as a segment and to which it can hybridise. of DNA of 1000 bases or more which is Benefits of FISH: present in a variable number of copies in comparison to standard DNA. To aid 1. It can turn almost any DNA into a analysis, the whole genome is fragmented probe. into many small regions and the array is 2. A much higher resolution compared arranged so the exact location of each to G-banding for identifying deletions, fragment within the whole genome can insertions, and translocation be identified. From this, the gene content breakpoints. of any imbalance can be established and 3. It can use cells in any stage of the the genes can be evaluated against the cell cycle as well as archived tissue. patient’s phenotype. 4. It can analyse results on a cell-by- In principle, to determine how copy April 2016 – cell basis. numbers differ from a reference (control) 5. Shorter turnaround times, as tissue sample: -INTGB does not need to be cultured for metaphase cells. 1. The sample and reference DNA Focus 56 2/5 are labelled with different coloured Single nucleotide polymorphism array: fluorescent probes (green and red). A single nucleotide polymorphism (SNP), a variation at a single site in DNA, is the 2. The two samples are applied to most frequent type of variation in the immobilised DNA on an array, and genome. For example, there are around complementary sequences bind. 50 million SNPs that have been identified Colour/Intensity information is collected in the human genome. Most of them are by a scanner. non pathological. The basic principles and techniques of SNP array are similar 3. Where there is no change in the to those of the array CGH, but the use of sequence copy number in the test SNP enables the collection of genotyping (patient) sample, there will be equal information in additional to standard binding of test and reference sample intensity data. DNA, and equal amounts of each Therefore, the chief advantages of SNP coloured fluorescence will produce a array over classical CGH array is that it net emission colour (yellow). can determine both CNVs and LOH (loss 4. For sequences where there has of heterozygosity i.e.: loss of genetic been a duplication in the test sample, material of one of the two parents), and there will be more green than red it can detect aneuploïdies like triploïdies, fluorescence and an overall green which represent approximately 5% of emission; conversely, deletions will chromosomal abnormalities responsible result in a reduced level of green for miscarriages. fluorescence relative to the red fluorescence from the reference sample, and a net emission of red light. Normal (diploid) Delection (lost of one copy Duplication (gain of one copy) Fig. 5: Profiles obtained by SNP array: Intensity and genotyping analysis Karyotyping vs array CGH and SNP array In principle, both karyotyping and arrays are genome-wide technologies which can be used to assess the presence of genomic imbalance such as copy number variations (CNVs). Although they may look like very different technologies, the primary difference between them is in April 2016 – the resolution, which is a measure of the level of magnification of the genome. A -INTGB standard G-banded karyotype usually Fig. 4: Principle technique of Array CGH has a resolution of around 5 Mb (i.e. it Focus 56 3/5 can detect changes of greater than a five FISH with a single probe is useful to million base pairs). Modern arrays act like confirm a suspected diagnosis of a well- a more powerful microscope. Depending described syndrome, such as Williams’ upon the particular array and how many syndrome, for example. DNA probes it uses, it is possible to detect Array CGH/SNP is indicated as first-line changes greater than 1 Mb (one million testing for: base pairs) at low resolution or changes as small as 10 kb (10 thousand base pairs) at 1.Unexplained learning difficulties high resolution. 2. Intellectual disabilities/cognitive Much smaller CNVs can be detected by impairment using higher resolution technologies, 3. Developmental delay. which means that more pathogenic CNVs 4.Behavioural problems including may be detected using modern arrays than autism spectrum disorders. through karyotyping. 5.Dysmorphism/multiple congenital As CNVs are relatively common throughout abnormalities suggestive of a the genome, numerous benign CNVs will chromosome abnormality. also be detected, so careful interpretation 6. Miscarriages (SNP array) and follow-up testing is needed. 7.For prenatal cases with abnormalities Clinical uses of karyotyping, detected during ultrasound FISH and array CGH/SNP In terms of the diagnostic yield in the diagnosis of mental retardation: Because of the differences in resolution and the various benefits and limitations of METHOD METHOD DIAGNOSTIC YIELD each technique, great care must be taken when deciding on which test(s) to request. Karyotyping and FISH 5 – 10% The appropriate test will depend on the clinical condition or syndrome suspected CGH arrays (BAC + 16.7 % of cases unexplained by and a carefully taken family history of arrays ) karyotyping/FISH genetic disease (pedigree). Consultation + 22.7 % of cases unexplained by SNP arrays with a clinical geneticist is advised. karyotyping/FISH In general, karyotyping is indicated as first- line testing for: It is important to note that the above are 1. Common aneuploidy assessment, only general recommendations. In several e.g. trisomies 21, 18 or a sex cases more than one test will be needed to make a diagnosis, with follow-up testing chromosome aneuploidy. sometimes required depending on the 2. Ambiguous genitalia/indeterminate results of the first-line test used.Nous gender. contacter 3. Delayed puberty/inappropriate secondary sexual development. Contact us 4. Short stature or amenorrhea in International Division females. 17-19 Avenue Tony Garnier 69007 Lyon-France 5. Isolated clinical features, e.g. cleft Tel.: +33 (0)4 72 80 23 85 lip, heart disease. Fax: +33 (0)4 72 80 73 56 6. Chromosome breakage syndromes. E-mail: [email protected] 7. Infertility. April 2016 – -INTGB Focus 56 www.biomnis.com 4/5 References: 1.
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