The Problem With Panels

Cystic fibrosis (CF) is a serious genetic condition that affects about one in every 3,500 people. It’s inherited in an autosomal recessive manner, meaning that both copies of the causative CFTR gene require a mutation to cause disease. Those with such mutations have defects of the exocrine epithelial cells in multiple tissues and experience symptoms including failure to thrive, chest infections, difficulty breathing, pancreatic insufficiency, infertility and more. The best way to minimize the impact of these symptoms is to diagnose CF early and begin treating it from a young age – but in certain cases, that’s easier said than done.

In some countries, including the United States, newborn screening programs can diagnose CF by detecting common mutations in the CFTR gene. But the “common” disease-causing mutations aren’t always the same (1) – and I noticed that, in this area, non-white patients are underserved. The molecular tests offered are often not representative of the sequence changes that are encountered in non-white individuals. Like many countries, the United States is a melting pot of ethnic diversity, so it’s important to have a good grasp of the diversity of mutations that arise – not just in white populations, but in other ethnicities as well. 

Where screening falls short

CF newborn screening has now been implemented in every single state in the USA, but identification of CF variants in non-white people remains suboptimal. If we know the sequence variants in each population, we can improve genotype-phenotype correlation, and that can affect a range of things including results reporting, counseling for families, accurate prognoses, and therapy decisions. Better yet, more familiarity with the mutation spectrum will allow us to optimize newborn screening programs based on the ethnic composition of the population. That can make a huge difference to patients, so my objective was to take the first step by establishing which mutations are present in non-white CF patients.

We’ve known for some time that many of those mutations were not being identified in routine screening. The panels as they exist today, both for carrier screening and for newborns, are based on early knowledge of the mutation spectrum in white and Ashkenazi Jewish patients. CF is most common in “white” – northern European Caucasian – individuals, with a frequency of about one in 2,500. It occurs less often in other populations (one in 11,000 Native Americans; one in 15,000 black people; and one in 35,000 Asian people) – but when it does, we often fail to find the relevant mutations during screening. That’s because we’re looking in the wrong place; the locations we target based on research in white populations aren’t the ones most commonly mutated in other ethnicities. To find them, we need to adopt a more comprehensive screening approach so that we can facilitate equity in diagnosis and improve our patients’ quality of life.

Delays and deterioration

Despite these genetic differences, disease presentation is the same regardless of a patient’s ethnicity. With newborn screening, CF patients in the United States are diagnosed at a median age of two to four weeks – and they can “hit the ground running” in terms of disease management. But in non-white patients, identification occurs significantly later. One of the hallmarks of CF is failure to thrive, so late-diagnosed patients gain less weight, experience less overall growth, and develop pulmonary issues. It’s a life-threatening disorder.

Non-white populations face another disadvantage: CF just isn’t at the forefront of the differential diagnosis. It’s much more likely that a physician would consider infectious diseases before a relatively rare genetic disease like CF. When I was collaborating with researchers in Thailand, I learned that some mothers will bring their child to the attention of a physician by saying, “I don’t know what’s wrong with my child, but she tastes salty.” That’s due to the abnormal salt and chloride metabolism typical of CF, but mothers sometimes notice that before physicians even think of the disease. So it’s important to improve our genetic tests, both to avoid delays in diagnosis and to ensure that we can unambiguously detect CF in our patients.

We can do better

Our work has really highlighted the limitations of panel testing in a diverse population. The next step is for newborn screening programs to consider more inclusive test approaches that improve diagnosis – and therefore enhance prognosis – for CF patients of non-white and mixed ethnicities. I think that, especially in ethnically diverse areas, it comes down to appropriate testing in each setting and for each patient. Every newborn screening program in the United States currently performs its own cost-benefit analysis. With screening, of course, you build in the assumption that you’re going to fail to detect some individuals in order to be cost-effective, but that should be minimized. I think that if you look carefully at available algorithms and regional demographics, you can achieve desirable sensitivities for all populations and avoid disproportionate disease burdens in minority ethnicities.

Doctors performing screening need to be aware that common panels don’t include some of the variants present in non-white populations. With the attention currently focused on personalized medicine, we can advocate for a more inclusive approach that could help propel equity in mutation detection. I personally believe that we should consider a more comprehensive approach like next-generation sequencing (NGS) – which doesn’t have to be much more expensive than our current tests, because the cost of sequencing is rapidly decreasing. The trick is to get people to consider these newer approaches, rather than simply opting for standard panels because they come to mind first, or because they’re assumed to be more economical. That doesn’t have to be the case – NGS may not only be more comprehensive, but also more cost-effective than our current methods (2). But regardless of how we approach the challenge, now that we better understand the diversity of disease mutations, I would like to see appropriate testing applied to every patient.