To the Editor: We write in reference to the article titled “An Empirical Estimate of Carrier Frequencies for 400+ Causal Mendelian Variants: Results From an Ethnically Diverse Clinical Sample of 23,453 Individuals” by Lazarin et al.1

We agree that ancestry-based carrier screening has significant drawbacks and may result in inequitable distribution of genetic testing and services. However, there are other issues to consider about carrier panels and the authors’ recommendations, some of which the authors briefly mention at the end of their Discussion.

Expanded carrier screening panels are often marketed directly to patients and have been increasingly adopted into clinical practice despite the lack of supportive clinical guidelines. Expanded screening does not meet all of the generally accepted criteria for population screening. For example, many of the included conditions do not cause significant health impairment, have highly variable clinical courses, and/or are at low frequency in all populations, regardless of ancestry.

The authors imply that the low cost of multigene panels is one reason to support this practice, but the true costs of expanded carrier testing need to be carefully examined. The assay described in this article tests for up to 417 mutations that have been associated with 108 conditions. The authors state that for the purpose of this study, only the most clinically significant 96 conditions were evaluated. The sensitivity for individual carrier detection is reported to be <10% for about one-quarter of the screened conditions; fewer than one-half have a carrier detection rate >50%. Given the poor sensitivity of the panel for many of the included conditions, follow-up testing of the reproductive partner may involve more extensive genetic testing such as whole-gene sequencing, which currently costs several hundred to thousands of dollars per gene. This is not a trivial concern because about one in four individuals will prove to be a carrier for at least one disorder.

The time investment for follow-up counseling and risk assessment should also be factored into follow-up studies evaluating the true cost of expanded carrier testing. The psychosocial impact of this expanded screening both in the short and long term needs to be considered and measured, as well as what carrier individuals and couples actually do with the information. Thus, carrier panels lower the cost of testing but could conversely increase the other costs of a carrier screening program.

Furthermore, the vast majority of conditions included in the panel are extremely rare; at least 30 conditions have an incidence of <1 in 1 million, and all but a handful occur in <1 in 5,000 individuals (ironically, α-thalassemia, perhaps the most common genetic disease in the world, is not included in the panel, we presume for technical reasons). Therefore the likelihood of follow-up carrier testing identifying a mutation in the partner is expected to be small.

In this study, 127 carrier couples (0.54% of all patients who underwent testing) were identified. Of note, 47 of these cases were positive for α-1-antitrypsin deficiency, with both the S and Z allele included in the panel. The S allele is known to be common in some populations and is not thought to be of much clinical importance unless paired with a more severe allele, and even then would be expected to cause a milder phenotype. On removing α-1-antitrypsin and the conditions for which screening guidelines already exist (through the American College of Obstetricians and Gynecologists and/or the American College of Medical Genetics and Genomics), such as cystic fibrosis, sickle cell anemia, β-thalassemia, spinal muscular atrophy, Tay-Sachs disease, the detection of carrier couples would drop to <0.1%. Included in this figure are conditions such as familial Mediterranean fever, factor XI deficiency, and GJB2-related hearing loss. Considering the mild and variable phenotype, age of onset, and treatment options for conditions such as these, significant ethical dilemmas accompany including these on a preconception/prenatal carrier screening panel.

Apart from the cost argument for increased screening, the authors suggest that the increasing population ethnic admixture is further justification for expanded “panethnic” carrier testing. Although we agree that the increasingly diverse background of the US population presents new carrier screening and risk assessment challenges, the possibility that this increased diversity may actually be decreasing the incidence of recessive genetic disease should be considered. The authors state that the “data show a number of severe Mendelian disorders are more prevalent than commonly understood.” On the basis of the presented data, there was nothing to show an increased incidence of disease. The carrier frequencies were higher than previously reported for some conditions and lower than previously reported for others, but there is no measure of prevalence of these recessive conditions.

The stated carrier frequencies do not take into account the possibility of ascertainment bias in what is not likely to be a random sample of the population. For example, a couple from a population with a low incidence of a particular recessive disorder might happen to have a family history of the disorder, which led them to undergo the testing in the first place. This would elevate the apparent carrier frequency in the population. The possibility of ascertainment bias is suggested by the identification of 78 homozygotes/compound heterozygotes. This could mean that at least some people are undergoing carrier testing as a means of diagnosing a genetic disease.

We hope we can reflect on the long held important considerations for implementing population screening programs and carefully weigh the pros and cons of expanding screening for our patients and for society.

Disclosure

K.S. and R.R. declare no conflict of interest. K.S. is an employee of the Department of Defense, but the views expressed are those of the author(s) and do not reflect the official policy of the Department of the Army, the Department of Defense, or the US government.