The Sequence 12/12-12/18
Major UK Study to Analyze Utility of Expanded Newborn Screening, The Use of NIPS in Prenatal Care, Polygenic Risk Scores and Colorectal Cancer, Risk-modifying BRCA1 Variant
Major UK study to analyze utility of expanded newborn screening
Genomics England and the UK's National Health Service (NHS) have joined together to participate in a newborn screening (NBS) study called the Newborn Genomes Programme, a study with the goal of screening 100,000 newborns for around 200 disorders, which will begin next year.
This sounds familiar.
It should! A similar study is being conducted across NewYork-Presbyterian's hospitals in New York City (NYC). You can see my post about it here. Both studies, the GUARDIAN study being conducted in NYC, as well The Newborn Genomes Programme in the UK, have the goal of screening 100,000 newborns for ~200 treatable conditions, the main goal being to prevent infant death in the case of a disorder that went undetected before birth. While in the US, screening for ~200 conditions is certainly an increase from the ~30-70 genetic conditions that standard NBS already covers, it’s an even bigger increase in the UK, where currently NBS only covers 9 genetic conditions.
Cool. How will this affect healthcare in the UK?
Well, based on how useful this vigorous NBS is shown to be at the end of the study, UK policymakers will decide if it makes sense to introduce whole-genome sequencing of newborns as part of routine care.
What’s the takeaway?
The Newborn Genomes Program will allow researchers to correlate the data gathered from 100,000 newborns with genetic conditions developed later in life. Genomics England and the NHS anticipate that approximately 3,000 children could be diagnosed with a known genetic condition earlier in life, allowing them to receive preventive care and increase their overall health.
Image credit: Metis Genetics
The use of NIPS in prenatal care
Noninvasive prenatal screen, or NIPS, is a blood test pregnant women receive to detect potential genetic conditions in their fetuses. This works because some of the fetuses’ DNA is also floating around in pregnant mom’s blood.
Here I summarize how the test works, and some why there’s some confusion around it.
What does NIPS look for?
NIPS screens for chromosomal disorders (aka aneuploidies) that are caused by the presence of an extra or missing copy of a chromosome. It looks for the most common chromosomal disorders, primarily trisomy 21 (aka Down Syndrome), trisomy 18, trisomy 13, and extra or missing copies of the X and Y chromosomes. Sometimes it will screen for additional chromosomal disorders as well. It’s important to note the word screen here.
How does it work?
The screening test looks at the DNA from fetal cells in mom’s blood sample. Now keep in mind, and this will be important, that there’s only about 1 fetal cell for every 1,000,000 maternal cells. This means there’s not a lot of fetal DNA to work with in the blood sample.
There are two different methods of performing the test that different labs use: Massively Parallel Shotgun Sequencing and targeted sequencing. I won’t get into the minute details of how each of these work, but it is important to realize there are different methods that different labs use; they’re not all equal. Both tests, in the end, are essentially looking at proportions. Using Trisomy 21 as an example, chromosome 21 usually makes up 1.5% of the total genome. If the test is showing that the DNA is made up of 2.25% chromosome 21, it is inferred that the fetus has an extra chromosome 21, and that the baby will have Down Syndrome.
With me?
Great! So what is this confusion about?
Since the screening is looking at fetal DNA from mom’s blood, it’s basically an estimate. Remember how I said there’s only about 1 fetal cell for every 1,000,000 maternal cells? Yeah. So when the data is looking for those changes in proportions of chromosomes, we’re talking about very very tiny percentages of more or less chromosomes, and these very small changes can easily be missed or misconstrued, leading to inaccurate results. This is why NIPS is considered a screening test; it is not diagnostic.
Confusion settles in when providers treat NIPS as a diagnostic test. NIPS is meant to give you an estimated risk for a chromosome abnormality- think ‘high’ or ‘low’. If NIPS comes back high-risk, the presence of a genetic condition still needs to be confirmed through a diagnostic test; i.e. a CVS or an amniocentesis.
Got it. Has this been an issue?
Yes. This article describes some experiences women have had when making decisions based on inaccurate NIPS results. It also talks about how the screening is not regulated by the FDA. Extremely important, because just this week The American College of Medical Genetics and Genomics (ACMG) put out a statement strongly recommending NIPS over other screening approaches for detecting common fetal trisomies for all pregnant patients. Previously, that recommendation was really only for women considered high-risk.
What’s the takeaway?
While NIPS is an incredible way to screen for chromosomal abnormalities with only a blood draw, and more recently only a finger prick, a screening test is just a screening test, and should be treated as such.
The utility of polygenic risk scores in predicting colorectal cancer
Researchers from University of Oxford analyzed 434, 587 individuals from the UK Biobank to evaluate the efficacy of combining polygenic risk scores with the colorectal cancer prediction model QCancer-10 in predicting the onset of colorectal cancer.
QCancer-10 is a prediction model that takes into account age, ethnic group, family history, and alcohol and smoking status as well as a few medical conditions into consideration to determine disease risk.
What is a polygenic risk score?
A polygenic risk score (PRS) is a number, or a ‘score’ that estimates an individual’s risk for a certain condition. They are used in conditions that are caused by changes in many genes, often coupled with environmental factors.
How are they determined?
Let’s use colorectal cancer as an example, because that is the health outcome studied in this article. Scientists created PRSs for colorectal cancer by comparing the DNA of patients with and without colorectal cancer to determine a ‘collection of genes’ that have more rare variation in the individuals with glaucoma that are not there in the individuals without colorectal cancer. Then, they can say if you have these ‘X’ number of genes, your PRS for colorectal cancer is increased.
What did they find?
The performance of the combined PRS-QCancer-10 tool compared to QCancer-10 alone did in fact modestly improve risk prediction. But that’s just it. It was really only a modest improvement.
What's the takeaway?
The researchers decided that the added benefit of adding PRS to QCancer-10 is not great enough to justify implementing PRS in addition to the QCancer-10 prediction model.
I’ve written about the utility of PRS to predict multiple medical conditions at this point; the different PRS having various degrees of utility in different conditions. It would be pretty amazing to be able to use a PRS (which is calculated from only a blood sample, by the way) to identify risks for common conditions, and especially for actionable conditions like colorectal cancer, where one can take preventive measures and increase screening. It is endlessly interesting to see how these predictions improve over time, changing the future of preventive health.
Genetic variant identified that modifies breast cancer risk in BRCA1-positive individuals
Chun Ding et al. analyzed 347 women with 185delAG BRCA1 mutations to understand potential breast cancer risk modifiers in individuals with this variant. 185delAG is one of the common founder variants in BRCA1 that I talk about here.
How did they do that?
The group looked for variable number tandem repeats (VNTRs), or repeat sequences in the DNA.
Interesting. What did they find?
The group identified seven VNTRs linked to younger breast cancer diagnoses. Remember this is all in patients with the same BRCA1 mutation.
What’s the takeaway?
This bite-sized Sequence update describes a new way to potentially identify which patients with the 185delAG BRCA1 mutation have an even higher risk of breast cancer at a young age than others with the same mutation. Like the onslaught of using polygenic risk scores to predict risk for conditions like cancer (above), the identification of additional risk factors can help us to improve risk assessment, this time in patients already at high-risk for developing cancer.