Chromosome Abnormalities And Genetic Counseling PdfBy Alice W. In and pdf 18.05.2021 at 21:49 7 min read
File Name: chromosome abnormalities and genetic counseling .zip
- Prenatal Genetic Counseling in Congenital Anomalies
- Gardner and Sutherland's Chromosome Abnormalities and Genetic Counseling
- Prenatal Genetic Counseling in Congenital Anomalies
- Molecular Diagnosis and Genetic Counseling in Ophthalmology
The impact of genetic variability on embryogenesis and fetus development established medical genetics as essential for the prevention of congenital anomalies, early detection and appropriate management. Advances in ultrasonography equipment and technique allow early detection of many congenital malformations. In addition, genetic testing can be performed in a prenatal setting on a variety of biological samples obtained by invasive and noninvasive procedures: chorionic villus sampling, amniocentesis, cordocentesis, or maternal blood collection i. In the past, only a small percentage of congenital anomalies had a readily identifiable etiology; genetic diagnostic procedures can provide at least some of the answers for the remaining unsolved cases.
Prenatal Genetic Counseling in Congenital Anomalies
The number of cloned genes and genetic loci associated with inherited retinal disease as a function of time. Data and figure courtesy of Stephen P. Example of somatic mosaicism for a cytogenetic abnormality in a 4-month-old boy seen at the ophthalmology clinic for evaluation of bilateral uveal colobomata. He had a history of failure to thrive, agenesis of the corpus callosum, conductive hearing loss, dysmorphic facial and skeletal features, small kidneys, and hypospadias.
Although a karyotype of peripheral blood lymphocytes was normal A , a repeat study on a skin biopsy specimen revealed almost complete absence of 1 homologue of chromosome 13 B. Because this abnormality would be predicted to delete the retinoblastoma gene locus on 13q14, the patient began surveillance for the presence of ocular tumor.
Karyotype images courtesy of Children's Hospital of Oakland. Fluorescent in situ hybridization FISH can be used to detect chromosomal deletions too small to be resolved using classic cytogenetic techniques.
In the technique, fluorescently labeled DNA sequences complementary to chromosomal areas of interest are hybridized to patient DNA. In this example, the green probe hybridizes to the center centromere of chromosome 11, while the red probe hybridizes to an area that includes the PAX6 gene.
Although a cytogenetic abnormality was detectable with G-banding in patient A, this deletion was too small to detect in patient B without the aid of FISH. Arrows indicate the deleted chromosome 11 absence of red signal.
Because the Wilms tumor suppressor gene, WT1 , lies in the same genomic region as the PAX6 gene, patients with such cryptic deletions also could have WT1 deletion and require tumor surveillance. Images have been digitally enhanced to show banding patterns of chromosomes in addition to FISH signals. A hypothetical, 3-exon gene. Recall that genes are composed of exons light gray boxes and intervening DNA sequences are removed by the splicing process introns, double lines between exons.
Specific DNA sequences can be amplified using specific primers denoted by open arrows via the polymerase chain reaction PCR. In most cases, the sequences that are amplified in molecular diagnosis are exons and the exon-intron boundaries dark gray rectangles.
These PCR products are then either directly sequenced or screened for mutations using technologies such as single-strand conformational polymorphism SSCP analysis or denaturing high-performance liquid chromatography dHPLC.
Any abnormality detected with these screening methods is then confirmed by direct sequencing. If a mutation were to occur deep within an intron or in the promoter region, it would go undetected.
Therefore, negative results from this kind of molecular analysis need to be interpreted with caution. UTR indicates untranslated region.
Blain D, Brooks BP. Molecular Diagnosis and Genetic Counseling in Ophthalmology. Arch Ophthalmol. The science of genetics is impacting medicine at a rapid pace. Through efforts such as the Human Genome Project and the HapMap Project, our knowledge of the human genetic landscape is rapidly evolving. The tools of genetic diagnosis, however, are not just for the laboratory scientist; they have the potential to revolutionize the way ophthalmology is clinically practiced.
Consider a family who has just had a child affected by what appears clinically to be Leber congenital amaurosis. Molecular diagnosis may offer this family a confirmation of the diagnosis, a definition of the recurrence risk, the possibility of future prenatal diagnosis, and even potential treatment trials. However, like any other tool in medicine, genetic tests have to be ordered and interpreted correctly and responsibly to avoid doing harm. This requires a thorough knowledge of the capabilities and the limitations of genetic testing,as well as a compassionate understanding of the counseling principles that go hand in hand with genetic testing.
We will begin by reviewing select laboratory tests and their relevance to clinical practice. Before a tube of blood is drawn or a sample taken, however, patients must be counseled as to the indications,ramifications, and alternatives to genetic testing.
We will therefore proceed with a discussion of the role of genetic counseling in ophthalmology and end with suggestions on how to integrate molecular medicine into your practice.
Humans have 22 pairs of homologous autosomes and 2 sex chromosomes XX in females, XY in males for a total normal chromosome number of During the process of meiosis, these chromosomes pair, recombine, and segregate such that each gamete normally receives 1 homologue of each autosome and 1 sex chromosome. The process of fertilization restores the amount of genetic material to the normal state.
During mitosis, chromosomes can be visualized microscopically after staining with an agent such as Giemsa G-banding. Each chromosome has a characteristic banding pattern, consisting of alternating light and dark bands. The resolution of this cytogenetic technique, known as karyotyping, ranges from approximately to bands, depending on the exact phase of mitosis examined.
Even at its highest resolution, however, karyotyping only provides a broad overview of the genetic landscape; each chromosomal band represents large segments megabases of DNA and multiple genes. Abnormalities range from aneuploidy a chromosome number not a multiple of 23 to more subtle abnormalities, such as partial deletion or duplication of chromosomes, insertions, and translocations.
Occasionally,individuals have chromosomal abnormalities in some, but not all, of their cells mosaicism, Figure 2. A more detailed view of chromosomal structure can be obtained by probing for specific genomic DNA sequences with fluorescently tagged probes fluorescent in-situ hybridization.
Fluorescent in-situ hybridization enables for the detection of smaller abnormalities that cannot be detected using traditional karyotyping. For example, in their recent review of chromosomal abnormalities in patients with aniridia, Crolla and van Heyningen 7 found that 13 of 30 patients studied had chromosomal abnormalities on the short arm of chromosome 11 11p13 that were only detectable by fluorescent in-situ hybridization.
Because 3 of these cases involved the WT1 tumor suppressor gene, this test had tremendous clinical impact on clinical tumor surveillance Figure 3. Newer technologies are allowing the interrogation of smaller and smaller pieces of the human genome, blurring the traditional boundaries between cytogenetics and molecular biology.
Because tumor progression is often accompanied by such chromosomal abnormalities, comparative genomic hybridization arrays may potentially be helpful in assessing prognosis and treatment in ocular oncology.
These changes are best analyzed with DNA sequence analysis. Genes are composed of several functional components Figure 4. Through a complex, regulated process of splicing, the intronic sequences are removed and a mature mRNA results.
This mRNA is, in turn, translated into protein. The transcription of these sequences is regulated by other DNA sequences ie, promoter and enhancer sequences. A typical scenario for molecular diagnosis is presented in Figure 4. Primer sequences complementary to sequence flanking the exons of a gene suspected to cause disease are used in the polymerase chain reaction to amplify exonic sequences ie, transcribed and translated into a protein product and the area of the exon-intron boundaries ie, the areas where splicing of the mRNA occurs.
These sequences are chosen to pick up changes that might affect the corresponding protein sequence or mRNA splicing. Alternatively, if a large number of polymerase chain reaction products are to be analyzed, screening indirect techniques such as single-strand conformation polymorphism analysis or denaturing high-performance liquid chromatography analysis can be used to screen for a change; direct sequencing can then determine the exact nature of the change.
While convenient for handling a large number of samples, these indirect sequencing methods are neither as sensitive nor as specific as direct sequencing. Typically, promoter, enhancer, and deep intronic DNA sequences are not amplified and are therefore not analyzed.
Reasons why a pathological sequence change is not detected using this technique could therefore include: 1 the gene studied is not the gene responsible for the condition; 2 the sequence change is outside of the region of the gene that is ascertained; or 3 the patient is heterozygous for a chromosomal deletion or rearrangement, such that 1 allele ie, the specific DNA sequence at this position on one of the chromosomes does not amplify with the polymerase chain reaction primers used.
Once a sequence change has been identified, how do we know that it is truly causative of the disease in our patient? Changes that are predicted to change 1 amino acid to another without otherwise affecting protein primary sequence missense mutations and those that are around splicing junctions can be more difficult to interpret.
Direct sequencing to identify mutations can be quite time-consuming and costly, especially if a disease can be caused by mutations in any one of a number of genes eg, retinitis pigmentosa or Leber congenital amaurosis. Hierarchical testing strategies have been proposed for genetic testing to improve efficiency and reduce cost. The use of high-throughput microarray technology also allows for the interrogation of multiple genes for a disease eg, retinitis pigmentosa or Leber congenital amaurosis in a single experiment.
Because the former may miss new mutations,negative results on this platform should be interpreted with caution. Such diagnoses generally evoke powerful feelings, such as fear, anxiety, helplessness, fatalism, loss,and guilt. Even with a long-standing diagnosis or a known family history,deciding to pursue genetic testing comes with emotional and practical ramifications. These should be addressed prior to and as a follow-up to testing, as part of genetic counseling.
It may first be useful to review some guiding principles of genetic counseling because these provide the framework in which genetic testing is offered to date.
Walker 16 cites 7 genetic counseling principles, many derived from principlism—an ethics theory based on the principles of autonomy, beneficence, nonmaleficence, and justice, used as guidelines to analyze specific ethical cases. While testing may be a favored option for a health care professional, the first principle remains that of voluntariness: patients ought to decide for themselves and their families whether genetic testing is indeed their best option.
Two other related principles are those of education—patients should have sufficient information at hand to make a reasonable decision for themselves—and complete disclosure of all relevant information by the health care professional since selectively withholding information is viewed as going against a patient's autonomy. In the same spirit, counseling should be both nondirective and empowering: options should be presented in a neutral manner, and patients should be given the ability to best use this information by the health care professional eliciting and exploring the patient's personal circumstances.
The last 2 principles of Walker are more universal, namely equal access to genetic services and protection of patient privacy and confidentiality. Genetic testing may be carried out for different purposes. These include to 1 confirm a diagnosis in an affected individual and sometimes assess the prognosis for that individual when phenotype the observed characteristics of a person -genotype the genetic makeup of a person correlations have been recognized; 2 determine the carrier status of an individual, either for an autosomal recessive or an X-linked condition; 3 ascertain a predisposition to a late-onset disease or establish a presymptomatic diagnosis; and 4 assist with preimplantation diagnosis, prenatal diagnosis, and newborn screening.
Such considerations ought to be discussed with the patient prior to testing because genetic testing generally requires informed patient or parental consent newborn screening being an exception. The extent of the discussion with the patient will, however, depend on factors such as information availability, receptivity and interest of the patient, and time constraints.
Some of this information should be revisited with the patient when results become available. Because of these complexities, we recommend that a professional well versed in genetics and genetic counseling eg, a clinical geneticist,a genetic counselor be involved when molecular testing is being considered. The discussion should first establish what will be tested gene[s],chromosomes, biochemical marker and the rationale for doing so. This should include a clear explanation of whether and how test results will influence disease management.
It should address which method will be used and what its benefits and limitations are. A piece of information sometimes requested by patients is test sensitivity the proportion of individuals with a specific diagnosis whose test results are positive.
When available, such information is important in anchoring patients' expectations as to possible test results. A different concept, the positive predictive value of a test the probability of being affected given a positive result , is equally useful in setting expectations. What these results may be positive, negative, of unknown significance and when they may become available should also be provided to the patient.
Patients should understand that not all genetic tests can give immediately useful information;in some cases, patients may be handed a result that cannot be interpreted.
Even in the presence of a known mutation, it may be difficult to predict disease severity in an individual variable expressivity. Testing costs and whether they are covered by insurance should be clearly ascertained because some genetic tests can cost several thousands of dollars. Patients should be aware that if an insurance company pays for a test, that company is entitled to the test results.
The risk for human error or possibility of test failure should be raised, however small it may be. This may prevent patient confusion if a new blood sample is needed, for instance. Finally, alternatives to genetic testing,whether they be clinical testing or no testing at all, should be presented to the patient; this should include the right to change one's mind and not receive test results in the end. Patients and their families should be made aware of the possibility to uncover nonpaternity and adoption in cases of linkage analysis or DNA testing involving several family members.
Gardner and Sutherland's Chromosome Abnormalities and Genetic Counseling
This new edition of Chromosome Abnormalities and Genetic Counseling is a thoroughly updated ands richly-illustrated resource, combining basic concepts of chromosomal analysis with practical applications of recent advances in molecular cytogentics. It gives counselors the information that will enable them to help concerned parents accommodate and adapt to their particular chromosomal challenges and to determine what may be, for them, the best course of action. M Gardner, author Auckland City Hospital. Lisa G. Access to the complete content on Oxford Medicine Online requires a subscription or purchase. Public users are able to search the site and view the abstracts for each book and chapter without a subscription. Please subscribe or login to access full text content.
Prenatal Genetic Counseling in Congenital Anomalies
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Molecular Diagnosis and Genetic Counseling in Ophthalmology
Medical geneticists and genetic counselors regularly see families attending the genetic counseling clinic with questions about chromosome abnormalities. These families may themselves have had a child affected with a chromosome condition; or, there may have been a history elsewhere in the family. The presentation may have been due to infertility or reproductive loss. Questions may include the following: What is known about this condition? What caused this to happen?
Background: World Health Organization estimates that million couple worldwide currently suffer from infertility. Recurrent pregnancy loss RPL is also another major concern. Chromosomal rearrangements play a crucial role in primary and secondary infertility and RPL. Methods: Karyotyping was performed for cases with the history of infertility and RPL over a period of one year.
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