One in four people is a carrier of a genetic disease. Carrier screening for inherited conditions began in the 1970s for specific conditions within at-risk populations. Now, many conditions are screened for within the general population to identify carriers of inherited conditions, even when there is no family history. Technological advances make it possible to conduct carrier screening for multiple diseases simultaneously and cost-effectively.
Carrier screening determines whether an individual carries a genetic variation (allele) associated with a specific disease or trait. It’s performed on individuals and couples during their reproductive years. Testing is usually conducted for diseases that both parents must be carriers for it to be expressed. By screening for variants in the same autosomal genes in a couple, carrier screening identifies those at higher risk of having a child with the disease.
Carrier screening’s primary goal is to support informed reproductive decision-making. Recessive disorders account for approximately 20% of infant mortality and up to 10% of pediatric hospitalizations in developed countries1. The risk of conceiving a child with a recessive genetic disorder is approximately 1–2% for any couple in the general population1.
Autosomal recessive (AR) traits or diseases require two copies of a specific gene mutation for the condition to manifest. Both parents must carry the variant, and when they do, there’s a 25% chance their child will have the disease, a 50% chance the child will be a carrier (which is the same when only one parent is a carrier), and a 25% chance they won’t have the disease or be a carrier. Genetic carrier testing allows parents to be screened for a range of genetic diseases, including these four.
Cystic fibrosis2—a progressive genetic disease that affects the lungs, pancreas, and other organs
An estimated 105,000 people have been diagnosed with cystic fibrosis in 94 countries (40,000 in the United States). It affects people of every racial and ethnic group. The carrier frequency in the general population is one in 45.
Sickle cell disease3— causes hemoglobin to clump together, changing the shape of red blood cells and leading to anemia and blocked blood flow
Approximately 100,000 Americans and millions worldwide have sickle cell disease. While the disease is present in all U.S. racial populations, it’s more common for those whose ancestors lived in Africa, South and Central America, and India. About one in every 365 Blacks and one in every 16,300 Hispanics have the disease. As far as carriers, about 1.5% of U.S. babies are born with sickle cell trait.
Tay-Sachs disease4— a condition where the absence of beta-hexosaminidase A (HexA) enzyme causes fatty substances to build up in brain and nerve cells, damaging the brain and spinal cord
Tay-Sachs disease is rare, with less than 5,000 people living with the condition in the U.S. While anyone can be a carrier, there is a higher frequency among some populations. About one in 27 people of Ashkenazi Jewish descent is a carrier. Those of Irish, Cajun, French Canadian, and Pennsylvania Dutch heritage also experience higher levels of the disease. The carrier frequency in the general population is one in 250-300.
Spinal muscular atrophy5—involves the loss of motor neurons in the spinal cord, affecting the central nervous system, peripheral nervous system, and voluntary muscle movement
Spinal muscular atrophy (SMA) affects approximately one in 10,000 births. Most SMA carriers do not have a relative with SMA and do not know they are carriers.6 Carrier frequency in the general population is one in 40-60.
The first recessive disorder screening was for Tay-Sachs disease in the Ashkenazi Jewish population, which led to other screening initiatives that initially focused on other population-specific diseases. Today, pan-ethnic carrier screening, which identifies high-frequency genetic disease carriers in the general population, is the most widely accepted practice.
Biochemical assays that diagnose, monitor, and manage metabolic diseases can be used to determine a person’s carrier status, including inborn errors of metabolism. This testing examines proteins and not genes. Proteins are less stable than DNA and are quick to degrade, so samples must be collected, stored, and delivered to the lab swiftly.
The growth of DNA sequencing methodologies that apply to carrier screening and the reduction of molecular test costs offers clinicians powerful options for each patient’s situation.
Targeted single-variant testing seeks a specific variant in a specific gene. It’s a good choice when testing family members of someone known to have the variant. Gene panels scrutinize several genes for variants. In the case of carrier screening, this type of test provides information on several potential conditions to those considering pregnancy.
Expanded carrier screening (ECS) has become a vital tool in identifying genetic disease carriers. This next-generation sequencing (NGS) technology pinpoints reproductive risks for up to hundreds of diseases simultaneously. Its comprehensive approach can be conducted with various panel sizes and assay technologies. ECS overcomes biases from incomplete family information and the challenge of estimating ethnic risk, particularly in multiethnic populations.
Carrier screening needs to meet the ACCE framework's four requirements for evaluating a genetic test—analytic validity (sensitivity, specificity), clinical validity (positive/negative predictive values), clinical utility, and associated ethical, legal, and social implications. Clinical validity is defined by detecting couples at increased risk of transmitting a genetic disorder to their offspring. Clinical utility is the possibility of providing them with reproductive options.1
Scientific societies, including the American College of Obstetricians and Gynecologists, recommend expanded carrier screening for all women and their partners who are planning a pregnancy.
When done before conception, screening allows couples to gain a comprehensive estimate of their genetic risk and the ability to make an informed decision about their reproductive life. Pre- and post-test counseling needs to be provided to offer explanations of the information the test provides, the limits, and the options available based on the estimated risk.
Education programs offer further support. Preimplantation genetic testing, in vitro fertilization with noncarrier donor gametes, and prenatal diagnosis are some reproductive alternatives to discuss after positive carrier screening results. Since ECS tests for many disorders, it’s not uncommon to test positive as a carrier. In rare cases, a carrier’s future health may be affected by carrier status.
While carrier screening usually focuses on couples, screening individuals can reduce concerns for people with known familial risk and provide valuable information if they change partners.
The technology available for Identifying carriers of serious diseases has changed dramatically since its beginnings. And it’s expected to continue to evolve as we make further advances in testing capabilities and our knowledge of genetic testing. Other aspects of carrier screening are poised to impact its future, too.
Increased screening—adding more conditions for screening and including more people in screening may help reduce the social stigma of carrier status and improve the general population's understanding and adoption of this life-changing genetic testing.
More reproductive options—the advent of new technologies, such as gamete intrafallopian transfer, pronuclear stage tubal transfer, tubal embryo transfer, and zygote intrafallopian transfer, will encourage more prospective parents to know their carrier status.
Technology progress—advances in state-of-the-art genetic testing will likely affect testing accuracy, speed, automation, and inclusiveness and challenge laboratories to keep pace.
Integrating genetic data—making test results available to clinicians through EHRs advances genomic medicine and precision health and improves outcomes; challenges exist, such as information storage standards, reliable genomic knowledge, and deciphering variants for clinicians.
Evolving technology offers critical information for better-informed reproductive decision-making and preventing inherited disorders for future generations. What does that mean for assays and the demand for reference material?
With expanded carrier screening commercial panels covering a vast number of genes (up to 1200), the challenge to source sufficient clinical samples to validate and assess assay performance on so many genes and their variants seems insurmountable. Until now, labs could only use clinical samples when they’re available or use nothing. Neither is good laboratory practice, nor do they follow ISO guidelines.
LGC has introduced the first 3rd party controls for carrier diseases. This highly multiplexed carrier screening reference material includes 54 pathogenic variants covering 48 genes responsible for cystic fibrosis, spinal muscular atrophy, sickle cell disease, Tay-Sachs disease, Phenylketonuria, cardiomyopathy, hemophilia A, fragile X syndrome, maple syrup urine disease, diabetes and many more.
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