Genotyping Vs. Sequencing: A Guide to Prenatal Screening


With so many labs offering prenatal and preconception testing for patients, it is difficult to keep up with all of our options as a provider. In a time where it feels like there is a new product coming out each month, and updates to old products just as frequently, the information we provide to our patients is rapidly evolving. As genetic counselors, we frequently hear the same concern echoed from the OBGYN, REI, and Internist population: “how do we choose carrier screening, and which one is best?”

We realize that lab sales reps, fellow healthcare providers, and your own reading provides many different forms of information about carrier screening.  To help navigate what is now available in the world of carrier screening, we wanted to break down one of the main differences across available tests, the distinctions between genotyping vs. sequencing.

Not all carrier screens are created equally. Although a lab may claim it will screen for the same condition as other labs out there, it is important to understand how they are screening for these conditions. The “how are they screening” could mean the difference in a residual risk of 1 in 280 to 1 in 5000.

Genotyping is a way of testing that looks for common disease-causing mutations that an individual may carry. Sequencing looks at an entire gene and can identify many pathogenic variants throughout, typically as much as 50% more than can be detected by genotyping.

By analogy, one way to think of this is that genotyping could identify the state capital in all 50 states, whereas sequencing can identify all of the towns in every state. The benefit of using sequencing on carrier screening rather than genotyping is that you have a significantly improved detection rate across all ethnicities, an increasingly important consideration in our society. Although it may sound like looking for just the common mutations is sufficient for “screening,” by not using the most up to date and comprehensive technology, you may be doing your patients a significant disservice.

One common example of how sequencing can provide both you and your patients more reassurance is with Spinal Muscular Atrophy (SMA). We know that all labs are screening for SMA by assessing the most frequent cause of the condition, a deletion of the SMN1 gene. So, most labs will assess a patient’s copy number of SMN1. In the Caucasian, Ashkenazi Jewish, and Asian patient populations, this can often significantly reduce their risks to be an SMA carrier. However, in the African-American population, which has a carrier frequency of 1 in 66, this means of testing still leaves a residual risk of 1 in 130, not all that reassuring.  Performing SMN1 copy number assessment in combination with sequencing on your patients with African-American ancestry can reduce that risk to 1 in 4300. By utilizing sequencing, we can provide markedly improved care in detection of common conditions that all major organizations, including ACOG, recommend we provide screening for.

This raises an important, general question – who is screening actually designed to serve? We know that genotyping used to be the standard of care for detecting cystic fibrosis in patients prior to the use of sequencing. While genotyping was good at assessing the risk of cystic fibrosis in most Caucasian and Ashkenazi Jewish patients, with detection rates commonly reported to be around 95%, the detection rate drops dramatically in the Asian, Hispanic, and African-American patient populations, who still have carrier rates of 1 in 87, 1 in 46, and 1 in 220, respectively. By providing sequencing to these patients, detection rates are commonly reported to be around 99% for all ethnicities, with residual risks decreasing to between 1 in 4500 and 1 in 6500. And since we don’t always know for sure what the ethnicity of any individual is, sequencing is simply a more a complete screening strategy than genotyping.   

Unfortunately, there are many labs that will market themselves as providing good screening options for a certain ethnicity but they do not hold up across the board for any additional ethnicities. Some labs will not even report a residual risk for additional ethnicities besides those for whom their test was initially designed. For example, there is a common lab that we see many groups using that will only report residual risk on the majority of the conditions for individuals of Ashkenazi Jewish ancestry. The shortcoming, of course, is that there is no way to provide reassurance on these conditions to patients who are not of Ashkenazi Jewish ancestry. For these patients, it is not reassuring that they are not carriers of mutations commonly found in the Ashkenazi Jewish population, as they were not expected to carry these mutations purely based on their ethnicity. Additionally, these tests may be marketed as being ‘pan-ethnic’ when they are not truly so.

The world of genetic testing is ever changing and this evolution is exciting. It can also be cumbersome and demanding on providers who are already being pulled in many different directions.