Genetic testing: an overview for clinicians
Male XY chromosomes. The Y chromosome is found in males and is shorter than the X chromosome. The latter has been labeled with a white glow that can represent a genetic mutation.
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Healthcare providers are constantly adapting to new discoveries about health and medicine. Being aware of the options available for patients is part of their role in everyday practice. Genetics is a complex, ever-advancing field that is becoming increasingly utilized in primary care; thus, a variety of genetic tests are now options that can be made available to patients when indicated. As our understanding of and ability to test the human genome advance at a rapid pace, primary care providers (PCPs) have the opportunity to integrate new information into everyday practice.1
A 2013 study of PCP perceptions of genetic testing conducted by the Council of Academic Family Medicine Educational Research Alliance (CERA) found that most of the participants felt that they were not knowledgeable about genetic testing but that genetic testing is of some value at present and will be increasingly valuable in the future.2 Genetic tests can now be used to assess risk for, screen for, diagnose, determine the prognosis of, and manage many hereditary diseases.3 Yet, many providers do not feel competent in the use of these tests.2,4 A recent survey of 315 primary care clinicians showed that more than 80% fail to initiate any patient discussions regarding genetic testing even once per month, and that only 19% had ever ordered genetic testing.4 These findings demonstrate the need for continuing education for healthcare providers about genetic tests and their common uses, with the aim of increasing provider confidence and so improve patient care.
The purpose of this article is to present information about five common genetic tests: karyotype, microarray, polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), and whole-exome sequencing (WES). The discussion of each test includes examples of its use in primary care, as well as precautions regarding the interpretation of results and patient education.
Karyotype is an older genetic test that is still commonly used to evaluate chromosomal abnormalities by sampling blood, amniotic fluid, chorionic villi, umbilical cord blood, products of conception, and bone marrow, among others. By isolating and pairing a patient's 23 pairs of chromosomes during mitosis, the test identifies large-scale chromosomal abnormalities (e.g., aneuploidy) and aberrations. Still commonly used in obstetrics to screen for chromosomal abnormalities in women with high-risk pregnancies, karyotype is also useful in primary care when providers suspect the presence of a hereditary condition like Down syndrome, Klinefelter syndrome, Philadelphia chromosome, trisomy 18, or Turner syndrome.5 (Some diseases caused by chromosomal abnormalities and others caused by genetic mutations are listed in Table 1.6-9)
PCPs may choose to perform chromosomal analysis when a woman has recurrent miscarriages or when an infant exhibits unusual features or developmental delays.5 In a meta-analysis of studies of the prenatal diagnosis of chromosomal aberrations, karyotype was found to have a sensitivity of 67.3% and specificity of 99%.10 PCPs must be aware of mosaicism for chromosomal aberration, in which not all of an individual's cells are affected by an abnormality. Although karyotype is very useful in diagnosing aneuploidy, it cannot predict outcome or the extent to which an individual will be affected by the diagnosis, so patient education before testing is essential to assist patients in making well-informed decisions.
Microarray is designed to recognize deletions, insertions, and duplications in DNA by looking for discrepancies in the amount of chromosomal material between a DNA sample and a control. This makes it possible to detect abnormal regions of DNA in which genetic material either is missing or has been added. Tagging target genes with fluorescent markers reveals differences between microarray patterns in a patient's sample and patterns in a control so that it is possible to determine whether or not an individual possesses a mutation associated with a particular disease.11 Although other substances can be sampled, in the clinical setting, blood is most often sent for analysis.
Microarray is a method of genetic testing that can accurately identify several chromosomal disorders, including almost all known deletion and duplication syndromes, and it recognizes abnormalities that are not detected by other chromosomal testing options. Microarray testing is used in pediatric patients with developmental delay, intellectual disability, multiple congenital anomalies, and autism spectrum disorders.12,13 Although in some cases, microarray has been replaced with DNA sequencing, it continues to be of value in the analysis of genetic diseases and cancer-linked mutations, and in pharmacogenetics.11 Providers and patients should be cautioned that a laboratory may report results as a “variant of unknown significance” (VOUS/VUS), which means that it is unknown whether the genetic variance detected is pathogenic or benign. Although microarray is useful in children with developmental delay or intellectual disability, interpretation of the results can be complex, and referral to a genetic specialist is recommended.12