Table 1.6 Residual risk values for diseases in Ashkenazi Jewish populations.
| Disease | 100% Ashkenazi Jewish carrier frequency | Detectability | Residual risk | Probability of affected fetus if parents pos/nega | |
|---|---|---|---|---|---|
| Gaucher disease | 1 in 15 | 0.95 | 1 in 281 | 1 in 1,124 | |
| Cystic fibrosis | 1 in 23 | 0.94 | 1 in 368 | 1 in 1,472 | |
| Tay–Sachs disease | 1 in 27 | 0.98 | 1 in 1,301 | 1 in 5,204 | |
| Familial dysautonomia | 1 in 31 | >0.99 | 1 in 3,001 | 1 in 12,004 | |
| Canavan disease | 1 in 55 | >0.97 | 1 in 1,801 | 1 in 7,204 | |
| Glycogen storage disease type 1a | 1 in 64 | 0.95 | 1 in 1,261 | 1 in 5,044 | |
| Hyperinsulinemic hypoglycemia | 1 in 68 | 0.90 | 1 in 671 | 1 in 2,684 | |
| Mucolipidosis IV | 1 in 89 | 0.95 | 1 in 1,761 | 1 in 7,044 | |
| Maple syrup urine disease | 1 in 97 | 0.95 | 1 in 1,921 | 1 in 7,684 | |
| Fanconi anemia | 1 in 100 | 0.99 | 1 in 9,901 | 1 in 39,604 | |
| Dihydrolipoamide dehydrogenase deficiency | 1 in 107 | >0.95 | 1 in 2,121 | 1 in 8,484 | |
| Niemann–Pick disease type A | 1 in 115 | 0.97 | 1 in 3,801 | 1 in 15,204 | |
| Usher syndrome type 3 | 1 in 120 | >0.95 | 1 in 2,381 | 1 in 9,524 | |
| Bloom syndrome | 1 in 134 | 0.99 | 1 in 13,301 | 1 in 53,204 | |
| Usher syndrome type 1F | 1 in 147 | ≥0.75 | 1 in 585 | 1 in 2,340 | |
| Nemaline myopathy | 1 in 168 | >0.95 | 1 in 3,341 | 1 in 13,364 | |
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
