by Rod Nowakowski, OD, PhD Genetic & Advanced Diagnostic Testing It is possible that genetic testing may reveal genetic conditions or predispositions unrelated to the original purpose of the test. These are called incidental findings. The American College of Medical Genetics has specified 59 genes in which incidental findings may have significant, treatable morbidity and hence, are considered "medically actionable." Those 59 genes are not among those that are typically investigated in most genetic tests for eye disease, but one test exception is a whole exome sequence (WES) in which the entire exome is sequenced. Recall that the exome includes all the genes that code for protein (about 22,000 of them). The 59 genes reside within the exome; medically actionable gene variants may be discovered anytime you order a WES. It is also possible to find abnormalities not related to those 59 genes that are still medically actionable in the sense that it is important knowledge for future health care. Here are three examples of incidental findings from patients seen recently at VisionAmerica: Case 1: A 35-year-old female with a corneal dystrophy.
For reasons related to her insurance coverage, a WES was ordered as opposed to a corneal dystrophy panel and that turned out to be fortuitous. She was found to have a variant in the BRCA2 gene (one of the 59) that put her at increased risk for hereditary breast and ovarian cancer. A copy of the report was given to her and she was strongly urged to share it with her PCP and gynecologist or obstetrician. Case 2: A 72-year-old male with a history of early onset, but not juvenile, macular degeneration. An initial XomeDxSlice for genes related to macular degeneration was ordered but was negative. Further testing was ordered that included a WES. He was found to have a pathogenic variant in the SDHA gene. This gene is a tumor suppressor gene. A pathogenic variant can cause loss of the suppressing function and consequently increase the risk for a variety of cancers-some benign and some malignant. For this variant, those cancers included a non-syndromic paraganglioma and gastrointestinal stroma tumor. Case 3: A 29-year-old female with achromatopsia. An initial XomeDxSlice revealed that she was heterozygous for a pathogenic variant in the CNGB3 gene. Since achromatopsia is autosomal recessive, she should have been homozygous. Several additional tests were ordered and one, a Whole-Genome Oligonucleotide Array, revealed that she had a 551 Kb pathogenic deletion in chromosome 16. Not everyone wants to know about their genetic risk factors and the test consent form has a section in which the patient must specify if she/he does not want to know any abnormal results from the 59 genes. To date, no one has declined wanting to know, but some do think carefully about it before answering that question. On the other hand, I have had patients specifically ask for more comprehensive testing than I might have had in mind and one person in particular refused genetic testing altogether because she was afraid we might find something she did not want to know about and she was not about to change her mind in spite of my arguments that detection of an unknown problem could be a good thing. Don't be surprised (and be prepared) if your patients express concern about these issues when you say that you want to refer them for genetic testing.
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August 2019
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