Carrier screening is the practice of detecting individuals and couples at risk of conceiving children affected by genetic (usually autosomal recessive) diseases. Modern genomics has changed the health economics of such genetic screening, with costs for DNA sequencing falling. The amortized cost of carrier screening for hundreds of genetic diseases is now far less than the cost of treating an affected child. This study offers clinical data from a large-scale use of expanded carrier screening panels that permitted assessment of hundreds of causal mutations for genetic disease. Because the rank ordering of carrier frequencies of these screenings can affect the design and prioritization of screening programs, the accuracy of this ranking is a public health concern.
The screening platform used high-throughput genotyping to identify disease-causing variants and corresponding wildtype alleles. In total, 417 disease-causing mutations associated with 108 recessive diseases were assayed and interpreted. The study sample included 23,453 individuals, referred from appropriate specialty clinicians, and included reproductive aged women and some of their partners. Diseases identifiable from the test platform ranged in severity from mild to incompatible with life. Routine screening for a possible carrier state was the indication in all individuals.
Whites constituted 60.6% of the population, and overall 75.0% were women. The median and mean ages of the participants were 33.0 and 33.63 years, respectively. Alleles associated with 96 recessive diseases (excluding mild conditions) were identified in the total cohort. Among the mild conditions, the most common was MTHFR deficiency. Of the total sample, 5633 individuals (24.0%) were heterozygous for at least 1 nonmild condition. A total of 7067 heterozygous states were identified. Thirty-eight individuals were homozygotes or compound heterozygotes for α1-antitrypsin deficiency; 9 for cystic fibrosis; 6 for GJB2-related DFNB1 nonsyndromic hearing loss and deafness; 5 for factor XI deficiency; 4 for Gaucher disease; 3 for familial Mediterranean fever; 2 each for carnitine palmitoyltransferase II deficiency, medium chain acyl-CoA dehydrogenase deficiency, sickle cell disease, and short-chain acyl-CoA dehydrogenase deficiency; and 1 each for chromatopsia, β-thalassemia, hexosaminidase A deficiency, familial dysautonomia, lipoamide dehydrogenase deficiency, Niemann-Pick disease type C, Pompe disease, and spinal muscular atrophy. When stratified by ethnicity, the carrier frequency ranged from 43.6%of Ashkenazi Jewish individuals to 8.5% of East Asians. About 5.2% (n = 1210) of individuals were carriers of 2 or more disorders. Most were heterozygous for only 2 conditions (4.3% of all those screened and 83.9% of multiple-disease carriers), although a small number were carriers of 3 (0.7% and 13.8%) or more than 3 conditions (0.1% and 2.3%). Ashkenazi Jewish individuals were most frequently identified as multiple carriers, with 13.3% carrying more than 1 genetic disorder. For “carrier couples” in which both partners were heterozygous carriers for the same condition, the most frequent conditions were α1-antitrypsin deficiency, cystic fibrosis, spinal muscular atrophy, sickle cell disease, and familial Mediterranean fever. Among carrier states detected, 76.7% and 69.0% were for diseases not included in American College of Obstetricians and Gynecologists (ACOG) and American College of Medical Genetics (ACMG) carrier screening guidelines, respectively. A total of 433 individuals would not have been identified as disease carriers based on the conventional ethnicity-based screening paradigms.
This study provides data on carrier frequencies for many rare disorders in multiple ethnic groups, which are an important resource for guiding diagnosis, treatment, and prevention of Mendelian diseases. Screening has often focused on a limited disorder list primarily determined by self-reported ethnic groups. This model may soon be obsolete because of the increases in mixed racial ancestry; opposition to use of racial and ethnic categorization in medicine; unknown or unreported ancestry due to limited family history knowledge, adoption, or other factors; and the decreasing cost of panethnic screening due to advances in genomics.
Department of Genetics, Counsyl, South San Francisco, CA (G.A.L., I.S.H., S.N., K.I., A.S.P., J.L.J., J.R.M., W.K.S., E.A.E., B.S.S.); Department of Pathology, New York University, New York, NY (J.L.J.); Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA (J.R.M.); Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT (P.P.); Departments of Computer Science (B.S.S.) and Statistics (B.S.S.), Stanford University, Stanford, CA