Genetic sequencing alone is not sufficient for newborn screening of metabolic disorders such as phenylketonuria, a new study indicates.
The study, “The role of exome sequencing in newborn screening for inborn errors of metabolism,” was published in the journal Nature Medicine.
Inborn errors of metabolism (IEMs), such as phenylketonuria, are a group of disorders caused by genetic mutations that affect the workings of metabolic enzymes. As these disorders become better understood, screening early in life has become increasingly possible, which enables prompt diagnosis, earlier treatment initiation, and better outcomes.
“There has been a lot of publicity about universal sequencing for newborns,” Jennifer Puck, MD, a professor at the University of California San Francisco (UCSF) and the study’s senior co-author, said in a university news story.
In California, an IEM screening program based on tandem mass spectrometry (MS/MS) has been ongoing since 2005. MS/MS is a technology that allows researchers to identify molecules by measuring their mass; aberrant levels of particular molecules can indicate certain disorders — for example, phenylketonuria can be diagnosed with MS/MS by detecting abnormalities in the levels of phenylalanine and tyrosine in the blood.
Genetic sequencing covers a variety of more recent approaches. For example, whole-exome sequencing (WES) enables sequencing all parts of the genome that code for protein. Sequencing technologies could be used for newborn screening (i.e., by looking for mutations that are known to cause IEMs).
“But,” Puck said, “claims that sequencing is the key to health have been made without the support of rigorous studies.”
Previous research has demonstrated that WES and similar technologies can identify mutations in people known to have a disease, but whether they are helpful in asymptomatic babies remains unknown.
“All of the prior studies of the utility of exome sequencing have started with a patient already in front of a doctor — in other words, a patient with a problem,” Puck said. “You start with a clue in hand, a person with a particular difficulty, and you’re trying to see if there’s an underlying genetic reason for that.
“When you switch to screening mode, you don’t have any clues. Most newborns look perfectly healthy.”
In this study, researchers analyzed data for the 1,334 babies with an IEM, among the nearly 4.5 million born in California from 2005 to 2013.
Overall, the sensitivity (true-positive rate) and specificity (true-negative rate) of MS/MS were at least 99%. In other words, screening based on MS/MS would correctly identify 99% of newborns with IEMs and the false positive rate would be 0.2%.
In contrast, the sensitivity of WES was 88%, and the specificity was 98.4%. This means that WES would miss about 160 of those 1,334 babies with IEMs, and incorrectly identify about 8,000 babies each year as having a metabolic disease.
“Across all IEMs currently screened for by MS/MS, WES had insufficient sensitivity and specificity for sole, primary use as a replacement for MS/MS,” the researchers wrote.
Several reasons could explain this discrepancy between the two techniques. By definition, screening by WES requires both that a disease-causing mutation is detected by the sequencing technology, and that the detected mutation is known to be disease-causing. This is a particularly relevant consideration in IEMs, which are often so rare that knowledge of their genetic basis is incomplete.
“These are well-studied single-gene conditions, but that does not mean we have found all the genes associated with them,” said Aashish Adhikari, PhD, the study’s first author, with UCSF’s Institute for Human Genetics and University of California, Berkeley.
Another limitation is the lack of diversity in research — most genetic studies of IEMs have focused primarily on people of northern European ancestry. In more diverse populations such as California’s, many disease-causing mutations may not have been analyzed.
Although MS/MS outperformed WES as a screening tool, the researchers said that the sequencing technology may still have uses. For example, it could help in cases where MS/MS identifies a problem, but the specific disease is not clear.
“If the current mass spectrometry testing comes out unclear, sequencing could reveal a gene variant that solves the mystery,” added Steven Brenner, PhD, one of the study’s senior co-authors, also with UCSF’s Institute for Human Genetics and the University of California Berkeley.
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