Carrier screening is typically offered to intended parents who are planning to have children or are already pregnant. The goal of carrier screening is to provide a more personalized risk of passing on genetic disorders and to allow intended parents the ability to make informed decisions about their reproductive health. Armed with information from carrier screening, they can weigh the value of prenatal testing during pregnancy versus assisted reproductive technologies such as in vitro fertilization with preimplantation genetic testing or explore the potential of adoption or gamete donation.
Back in the day, carrier screening was simple. The Punnett square was our most advanced tool.
Couples who both carried a disease-causing variant in the same gene had (and still have) a one in four (25%) chance of having an affected child.
However, with the passage of time and advancements in the field of genetics, things became a lot more complicated.
One Gene - One Disease
We learned that one gene doesn't necessarily cause only one genetic condition. The CFTR gene was once associated with “cystic fibrosis”; now it is associated with “CFTR-related conditions'', a group of diseases caused by CFTR variants that don’t meet diagnostic criteria for cystic fibrosis. Congenital absence of the vas deferens (CAVD) is the most well-characterized of these disorders, with 80% of affected individuals being found to have CFTR variants. Now, testing for CFTR isn’t just used to identify carrier couples or those suspected of having cystic fibrosis. It is recommended that men who have a history of infertility undergo CFTR testing to determine if they carry CAVD-causing genetic variants that could explain their infertility.
Asymptomatic Carriers
Once upon a time, carriers were not expected to experience symptoms of a disease. Yet decades of research have grown the list of conditions in which carriers can experience symptoms related to having a single non-working gene.
Condition | Possible symptoms in carriers |
Cystic Fibrosis | Mild recurrent respiratory infections, nasal congestion, digestive issues, or an increased risk for chronic pancreatitis |
Sickle Cell Disease | Under certain conditions such as high altitudes or extreme physical exertion, dehydration may lead to a sickle cell crisis |
Beta-Thalassemia | Mild anemia or fatigue |
Fragile X Syndrome | An increased risk of developing primary ovarian insufficiency, fragile X-associated tremor/ataxia syndrome, and fragile X-associated neuropsychiatric disorders |
Tay-Sachs Disease | Milder neurological symptoms such as muscle weakness or unsteadiness |
Duchenne Muscular Dystrophy | Cardiomyopathy in female carriers |
It's important to note that carrier status does not always result in symptoms and carriers of genetic variants may remain entirely asymptomatic throughout their lives. Additionally, the severity of symptoms can vary widely among carriers.
Type of Variant
The intent of carrier screening was never to diagnose an intended parent with a condition.
But we have learned that the same gene can have variants that pose different risks to and effects on a parent and their child. Examples include COL11A2, COL4A3, CAPN3, CLCN1, GJB2, and POLG, which can cause autosomal dominant and autosomal recessive conditions.
In these cases, the discussion now includes:
An increased risk to a child, from one in four (25%) to one in two (50%)
A diagnosis for the parent
Follow-up recommendations for the parent, including appropriate specialists and screening
Potential testing of other relatives due to an increased risk to family members
Same Variant - Different Outcome
One of the many goals of genetic counseling is to offer insight into the potential risk for disease and how the disease could affect a future child. Genetic conditions are inherently variable, meaning that a change in a gene may not consistently cause the same symptoms or the same degree of symptoms, even within the same family. We don’t know why this is; perhaps there are genetic changes in other genes that affect the clinical picture, or there are changes in non-gene areas of DNA that impact the function of the gene that carries the variant, or maybe there are environmental factors that play a part in how a disease presents.
This is particularly true for the ALPL gene, which is often on carrier screening panels. This gene causes hypophosphatasia (HPP), a disorder of bone mineralization. There are six overlapping forms based on age of onset and severity that range from immediately before and after birth to adulthood. All forms except the perinatal/severe form of HPP can occur in patients with one or two ALPL gene variants and what you see in one family member can be vastly different from what you see in another.
Help is Available
Time and advancements brought complexity, yet it also allowed genetic counselors to update their tool belts. Today we use PubMed for the most recent research, professional colleagues in the clinic, laboratory, and industry, and patients who offer their lived experiences. We use them so you can use us.
P.S.
Writing this blog reminded me why I love genetics. In college, I was drawn in by the fact that one changed base in a gene (i.e. one letter in a word) could have such an impact on how a body develops and functions. That gene was HBB and that condition was sickle cell disease. Twenty-eight years later, there are so many seemingly “simple” factors that, when put together, make this one hell of a complex and fascinating field. I love genetics and I love helping people understand all of the potential implications, at least as we know them today.
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