Healthy Babies — Newborn Genetic Screening -

Last time we talked about various approaches to high throughput sequencing techniques for personalized medicine. [Effectively, this is a way to learn all of the base pair letters in a person’s DNA code, this generates lots of data that can then be used to make assessments about the health of that individual]. There two areas in particular where emerging techniques and new standards are likely to have a big impact: Newborn Genetic Screening and cancer genetics. Today we’ll talk about the first area.

Newborn Genetic Screening for serious diseases that may be unnoticed at the time of birth has been around for a long time. In fact 2013 marked the 50th anniversary of systematic screening for phenylketonuria (or PKU). PKU is a serious disease that can lead to intellectual disabilities and national advocacy groups worked hard to take advantage of chemical tests that were cheap, fast, and minimally invasive (originally the urine was tested, now more likely a small needle prick on the heel to get a drop of blood) to determine if newborns, who would not have signs of the disease, were likely to have it. Treatment could be initiated quickly and many of the harmful effects avoided. In some cases treatment is very simple, i.e. regular monitoring of phenylalanine and diet.

Screening babies is now required by law and is controlled by state health officials. There was great variation in methods and the diseases screened for from state to state but more recently attempts to standardize the approach among states has gained traction. A “blue-ribbon” committee in 2006 recommended a uniform set of diseases and methods that included nearly 60 conditions with 29 of them mandatory. There is a “uniform panel” of disorders recommended by the Secretary of the Department of Health and Human Services on the advice of a federal advisory committee called the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children. This has yet to be instituted nationally, although most states strive to adhere to the national standards. In Illinois babies are screened for 44 genetic disorders like PKU and Cystic Fibrosis. More diseases are added by legislation often from patient-driven initiatives.

Geneticists and peditricians care for children with complex genetic disorders and are strong advocates for genetic screening. Many are actively engaged in research designed to help us understand the relationship between abnormal genes and the manifestations of the associated diseases as well as what the most effective therapies are. In Illinois hospital departments screen for 34 genes for specific diseases and gene panels for other diseases are available, including 70 genes for an Epilepsy panel. These tests are done with massively parallel sequencing or Next Generation Sequencing as we discussed in the last post. This approach has such a high throughput that it allows many more genes for complex disorders (e.g. Epilepsy) to be examined in many patients.

Since PKU and the other conditions are caused by mutations in genes it seems logical given that the falling cost of sequencing the entire genome (all 3 billion of our base pairs designated A,T,C, or G), would be the best way to look for unsuspected diseases

[read more on genome sequencing here and about DNA in general here]. In fact that is not done at the present time. There are a lot of complicated issues at play in this field.

At the moment screening is done in variety of ways; recent advances even allow a cutting edge method called tandem mass spectroscopy to be used to identify disease related proteins. In some diseases such as Cystic Fibrosis there are many mutations in the gene associated with the disease (the CFTR gene), but only a few of them are screened. There are perhaps nearly 2000 mutations (called alleles), but screening for all of them is not practical. So using test reagents (called allele specific oligonucleotides) to look for the 40 or so most important mutations is the general approach.

Sequencing specific genes is currently done, in particular when a separate genetic screen shows a disease related genetic problem. Knowing the specific mutation (a mistake in the DNA code) can be crucial in establishing the diagnosis and selecting the correct therapy. The use of complete sequencing, or array based examination of disease associated Single Nucleotide Polymorphisms (abbreviated as SNPs) where up to a million can be examined at a time, could solve this by allowing a complete examination of this gene or even all of the genes. The potential impact of this type of screening is enormous and the National Institutes of Health is sponsoring a major effort to determine if this approach will work. [Read more about these efforts here and here].

However, there are many potential problems, not the least of which is trying to determine when unsuspected mutations are discovered whether or not they are the cause of the disease, just effecting the disease severity or are unrelated. Sometimes it is difficult to know when a difference in DNA sequence is an inconsequential variation or a dangerous disease related mutation.

Ethical issues surrounding the determination of complete sequences for patients are also very important as well. These issues will be brought into sharp focus if sequencing the whole genome becomes the norm for newborn genetic screening.

Who will own the data — the newborn, the parents, the insurance company, the hospital?

What will happen with observations of consequence but unrelated to the diseases on the uniform panel of conditions?

Will we not even bother to have a “list” of diseases to screen for but rather look for problems in all genes with a known disease association?

We can expect that if this approach is taken on in a widespread population base, for example nationally for all newborns, that information linking mutations to specific disease outcomes will expand rapidly and extensively! As in the past when great technological advances pose ethical dilemmas we manage to muddle through them, even if it isn’t always pretty.

From the beginning of newborn screening programs clinicians and scientists have tried to be very thoughtful about looking at the question of what diseases to screen for. They have limited themselves to disorders for which a specific and sensitive test exists, where the natural history of the disease is understood and where an effective treatment exists. Whole genome sequencing, whole exome sequencing, and SNP analysis will have a profound impact on the first two of these and one might expect from that alone the number of disorders that are screened and number of babies identified with treatable conditions will increase, ultimately making us a healthier society.

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Originally published at

Phil Iannaccone is a Professor of Pediatrics and Pathology at Northwestern University Feinberg School of Medicine.