1 in 2,684
a One parent is positive and one parent is negative by carrier screening.
Source: Modified from Scott et al.564
However, the limitations of ethnic‐based carrier testing were revealed by a genetic ancestry analysis of >93,000 individuals having expanded carrier testing using a 96‐gene panel.565 Nine percent of those tested had an ancestry from a lineage inconsistent with self‐reported ethnicity.
Multiple published reports on preconception or prenatal expanded carrier screening using large but variable‐sized gene panels overwhelmingly support this approach above ethnicity‐based testing.545, 549, 566–572
Although not currently required in preconception carrier screening, testing for hereditary cancer risk should be considered. A personal or family history of cancer as well as ethnicity currently serves as an indication for screening. Autosomal dominant disorders are otherwise not usually subject to screening. In a study of 26,906 individuals in the Healthy Nevada Project screened for BRCA‐related breast and ovarian cancer, Lynch syndrome, and familial hypercholesterolemia, 1.33 percent were found to be carriers of pathogenic or likely pathogenic variants.573 Moreover 90 percent of carriers had not been identified previously, and only 25.2 percent had a relevant family history. These three disorders determined by screening (not family history) are not usually considered for prenatal diagnosis or preimplantation genetic testing. However, other autosomal dominant disorders with manifestations in childhood (e.g. multiple endocrine neoplasia type 2B, familial adenomatous polyposis, long QT syndrome, cardiomyopathy) do qualify for preconception, preimplantation, and prenatal testing. A study of 23,179 individuals with a family history of cancer had next‐generation sequencing using a 30‐gene panel.574 A total of 2,811 pathogenic variants were found in 2,698 individuals for an overall pathogenic frequency of 11.6 percent. For those of Ashkenazi Jewish descent three‐quarters of the pathogenic variants in the BRCA1 and BRCA2 genes would have been missed if only the routine three common founder mutations were tested.
Geneticists and genetic counselors will attest to the frequent challenges they encounter faced by their patients' difficulty comprehending genetic test results, implications, and options. On the heels of the technologic advances in genetics have come commercialization in the form of direct‐to‐consumer (DTC) testing. Few patients are cognizant of the commercialization realities that include selling of their data, receiving misleading results, being faced with incorrect, false‐positive or false‐negative results, a lack of informed consent, confidentiality, and privacy.575–580 There is a wide spectrum of laws that govern genetic testing in most countries, with special reference to laboratory accreditation, staff certification, genetic counseling requirements, and informed consent.
In one study of identical twins there was a lack of concordance between laboratories.581 In an illustrative case, the result provided was actionable, but no action was taken by the recipient of the DTC communication.582 Ethical breaches, including testing of children, further complicate DTC practices.583
Professional organizations, aware of all these issues, have discouraged the use of DTC genetic testing. Position statements have accordingly been issued by the American College of Obstetricians and Gynecologists,584 the American College of Medical Genetics and Genomics,585 the Joint Society of Obstetricians and Gynecologists, and the Canadian College of Medical Genetics.586 A range of laws exist in Europe, with France and Germany banning DTC genetic testing.587 Serious concern has been expressed about the ethical, legal, and regulatory challenges of DTC testing in Ireland588 and Europe.589
A family history of a genetic disorder
The explicit naming of a specific genetic disorder when the family history is being discussed facilitates evaluation and any possible testing. Difficulties are introduced when neither family nor previous physicians have recognized a genetic disorder within the family, sometimes revealed by expanded carrier screening591 or whole‐exome sequencing.592 Such a disorder may be common (e.g. factor V Leiden deficiency) but nevertheless unrecognized. Clinical clues would include individuals in the family with deep‐vein thrombosis, sudden death possibly due to a pulmonary embolus, and yet other individuals with recurrent pregnancy loss.593 Venous thromboembolism is the third leading cause of cardiovascular death in the United States, and provides additional insights into the genetic basis of unprovoked pulmonary embolism. Using whole‐exome sequencing in 393 affected individuals and 6,114 controls, Desch et al.594 identified four genes (PROS1, STAB2, PROC, SERPINC1) with pathogenic variants, expanding the need for genetic testing given the history of thromboembolism.
For some families, individuals with quite different apparent clinical features may, in fact, have the same disorder. Seventeen cancers in different organs in family members may not be recognized as manifestations of the same common mutation. In hereditary nonpolyposis colon/rectal cancer, various family members may suffer from other cancers including the uterus, ovary, breast, stomach, small bowel, ureter, melanoma, or salivary glands. Analysis of the five culprit genes in the proband would enable detection of the mutation, which could then be assayed in other family members at risk. In another example, there may be two or more deceased family members who died from “kidney failure,” and another one or two who died from a cerebral aneurysm or a sudden brain hemorrhage. Adult polycystic kidney disease (APKD) may be the diagnosis, which will require further investigation by both ultrasound and DNA analysis. Moreover, two different genes for APKD have been identified (about 85 percent of cases due to APKD1 and close to 15 percent due to APKD2),595 and a rare third locus is known.