Study population

This study sample included 23,453 individuals. Referral sources included family practitioners, geneticists, genetic counselors, obstetricians, perinatologists, and reproductive endocrinologists. Documented informed consent, including consent to research, was required of all patients and is on record at our facility. Institutional review board exemption is applicable due to de-identification of the data presented (45 CFR part 46.101(b)(4)). Genetic counseling was made available at no cost to all tested individuals.

Funding was performed as fee-for-service, typically reimbursed through third-party payers.

Population demographics

Self-reported ethnicity is summarized in Table 1. Caucasians constituted 60.6%, and 75.0% were female. Most samples came from within the United States; a minority came from Australia, Canada, England, or New Zealand.

Table 1

Carrier statistics categorized by self-reported ethnicity

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The median age was 33.0 years and mean age was 33.63 years. Most (n = 17,865) of the individuals were from 21–39 years of age. A small percentage was under 21 years (1.6%) or over 45 years (2.8%).

Disease carrier states

Alleles associated with 96 recessive diseases (excluding mild conditions) were identified in our 23,453 patients (Supplementary Table S1 online). Among the mild conditions, the most common was MTHFR deficiency, with a frequency of 1 in 1.9. Because these conditions typically have limited reproductive decision-making significance, they will not be considered further in this analysis. All subsequent analysis considers only those diseases listed in Supplementary Table S1 online.

Of the total sample, 24.0% of individuals (n = 5,633) were heterozygous for at least one non-mild condition. A total of 7,067 heterozygous states were identified. Carrier statistics are fully reported in Supplementary Table S1 online.

Seventy-eight individuals were identified as homozygotes or compound heterozygotes for the following conditions: α-1-antitrypsin deficiency (n = 38), cystic fibrosis (n = 9), GJB2-related DFNB1 nonsyndromic hearing loss and deafness (n = 6), factor XI deficiency (n = 5), Gaucher disease (n = 4), familial Mediterranean fever (n = 3), carnitine palmitoyltransferase II deficiency (n = 2), medium chain acyl-CoA dehydrogenase deficiency (n = 2), sickle cell disease (n = 2), short chain acyl-CoA dehydrogenase deficiency (n = 2), achromatopsia (n = 1), β-thalassemia (n = 1), hexosaminidase A deficiency (n = 1), familial dysautonomia (n = 1), lipoamide dehydrogenase deficiency (n = 1), Niemann–Pick disease type C (n = 1), Pompe disease (n = 1), and spinal muscular atrophy (n = 1). The published specificity of the testing method suggests that these are “true positives” and merit further examination of clinical correlations.¹² Review of clinical notes found at least two individuals with previously known diagnoses, for Gaucher disease and deafness. Another individual reported a history of sickle cell disease but did not specify whether this was familial or personal. All others did not report diagnosis information in their test requisitions and selected the routine carrier screening indication. For asymptomatic individuals with conditions such as α-1-antitrypsin deficiency, results could be used to guide appropriate surveillance.

Carrier rate variability by ethnicity

Frequencies of positive results varied by ethnic group (Table 1). On average, 24.0% of individuals were positive for at least one condition. When stratified by self-reported ethnicity, this frequency ranged from 43.6% of Ashkenazi Jewish individuals to 8.5% of East Asians. For ethnic groups like the Ashkenazi Jewish, this frequency is unsurprising given the availability of screening for many conditions found in this group.

Multiple-disease carriers

Some individuals were heterozygous for multiple disorders (Table 2), with ~5.2% (n = 1,210) found to be carriers of two or more disorders. Most were heterozygous for only two conditions (4.3% of all screenees and 83.9% of multiple-disease carriers), although a small number were carriers of three (0.7 and 13.8%) or more than three conditions (0.1 and 2.3%). Ashkenazi Jewish individuals were most frequently identified as multiple carriers, with 13.3% of all tested Ashkenazi Jews carrying more than one genetic disorder. These values are unsurprising, as population geneticists have long known that individuals carry on average 4–5 recessive lethal alleles.^10,15 Put another way, the average number of positive results for recessive lethals in this panel is only (0 × 0.694 + 1 × 0.244 + 2 × 0.053 + 3 × 0.008 + 4 × 0.001) = 0.378; sequencing the entire genome of each patient would reveal ~10 times as many lethal recessives on average.

Table 2

Carriers of multiple diseases categorized by self-reported ethnicity

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Carrier couples

Some pairs of patients identified themselves as couples. In this set, we found several “carrier couples” in which both partners were heterozygous carriers for the same condition. Table 3 lists disorders identified in carrier couples at elevated risk of passing the carried disorder to their children.

Table 3

Carrier couples identified

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Comparison to previously published carrier frequencies

Table 5 shows, for each ethnic group with n > 500 in our data set, the 10 most commonly detected diseases, along with our estimates and literature estimates for carrier frequency. For a handful of disease/ethnicity pairings, we were unable to find a previously published estimate. For most diseases, particularly in the well-studied Northwestern European and Ashkenazi Jewish populations, our estimates are similar to previously published estimates of carrier frequency. However, there are some notable outliers.

We observed significantly higher carrier frequencies than expected for severe diseases in several populations. In particular, we find a cystic fibrosis carrier frequency of 1 in 40 among south Asians (95% confidence interval 1 in 29–64), in marked contrast to the published 1 in 118 rate.²¹ This corroborates reports that cystic fibrosis is under-reported in the South Asian population.²² Another notable outlier in both Ashkenazi Jews and East Asians is carnitine palmitoyltransferase II deficiency, which appears as a notably frequent disease (1 in 43 in Ashkenazi Jews and 1 in 378 in East Asians), although the literature marks it as very rare.²³ Finally, we detect Smith–Lemli–Opitz syndrome (SLOS) at a significantly higher than expected rate in all European populations, in Hispanics, and Middle Easterners (1 in 123 from literature vs. 1 in 68 here; 95% confidence interval 1 in 60–78). Prior work suggests that a higher carrier frequency for SLOS than that computed from its birth prevalence is reasonable, because mutations in DHCR7, the causative gene for SLOS, may cause significant fetal mortality.²⁴

In the African-American population, we observe significantly reduced carrier frequencies relative to literature statistics for 7 of the top 10 diseases, other than sickle cell disease, α-1-antitrypsin deficiency, and cystic fibrosis. Comparison to prior data in this population is confounded by significantly varying levels of ethnic admixture in the African-American population; it is possible that our study population is genetically distinct at these loci relative to prior studies.¹⁶ Although we have not attempted to estimate admixture proportions in our study patients, it may be an interesting avenue for future research.

Similarly, in the East Asian population, we find much lower carrier frequencies for Pendred syndrome (1 in 252 vs. 1 in 51) and Pompe disease (1 in 366.5 vs. 1 in 112). We suspect two independent causes for the discrepancy. First, general-population screening data are not available for these diseases in this population; consequently, statistics are often derived from targeted study populations enriched in the mutations in question.²⁵ Second, the East Asian population displays sufficient genetic diversity (e.g., population structure among Han Chinese, Koreans, and Japanese) to have confounded results in earlier genetic studies.²⁶ Our self-reported ethnicity data do not have sufficient detail to identify this structure.

We note that direct comparison between our results and the published literature can be difficult due to previously mentioned statistical considerations and differing population substructures. As an example, carrier frequencies in Middle Eastern subpopulations reported in previous literature can vary widely and could also be substantially different from frequencies in Americans of Middle Eastern origin. Therefore, the references in Table 5 are not meant to present an exhaustive review but to provide context for comparison. The specific ethnic distributions merit further examination because robust data are unavailable for many diseases.

Comparison to ACOG/ACMG guidelines

ACOG and ACMG guidelines aim to identify couples with a minimum a priori carrier risk, based on ethnic background or general-population disease prevalence. The ACOG recommends at least a subset of patients be offered carrier screening for CF, hemoglobinopathies, Tay–Sachs disease, familial dysautonomia, and Canavan disease.^1,2,6,7,8 ACMG recommendations add SMA, Fanconi anemia Group C, Niemann–Pick disease type A, Bloom syndrome, mucolipidosis IV, and Gaucher disease type 1.

For their intended purposes, the ACOG and ACMG guidelines serve well. However, our results demonstrate that most of the heterozygous states we identified fall outside these guidelines (Tables 4 and ​55). Because the current thought is that the average individual is heterozygous for at least five recessive diseases, this is not surprising.¹⁵ By comparison, screening most Caucasians only for CF, as is recommended by the ACOG, yields a 4% positive rate. Focusing on a smaller number of conditions and on targeted ethnic groups means that most individuals at elevated risk are not identified.

In particular, the data show that a number of severe Mendelian disorders are more prevalent than commonly understood (Table 5), are often present outside their characteristic ethnic groups (Table 4), and are not covered by current screening guidelines (Table 5). For example, we find a SLOS carrier frequency of 1 in 68.2 in our overall population, almost twice the previously reported 1 in 123 carrier frequency.²⁷ Neither the ACOG nor the ACMG currently recommend offering screening for this severe condition. In contrast, the ACMG does recommend screening for SMA, with a similar worldwide carrier frequency of 1 in 57 (our data) or 1 in 54 (literature).²⁸ Indeed, in the Northwestern European population, we find indistinguishable carrier frequencies for SLOS and SMA: 1 in 50.3 and 1 in 49.9, respectively. Carnitine palmitoyltransferase II deficiency presents another illustration of a disease with a frequency worthy of consideration of wider screening. In our Ashkenazi Jewish population, the carrier rate was higher than several other conditions currently included in screening guidelines (Table 5).