Exome sequencing may not be as reliable as standard blood testing for identifying rare diseases in newborns.
A recent study, led by researchers at the University of California (UC) Berkeley and UC San Francisco, used whole exome sequencing of historical DNA data to test for rare metabolic disorders in newborn babies. The scientists discovered that there were far more diagnostic errors when compared to standard blood-based testing.
'There has been a lot of publicity about universal sequencing for newborns,' said Dr Jennifer Puck, professor of paediatrics at UC San Francisco and co-senior author of the study. 'But claims that sequencing is the key to health have been made without the support of rigorous studies.'
In California, every newborn is tested for rare, inherited metabolic conditions, where identifiable symptoms are not yet evident. Following a simple heel-prick blood test, tandem mass spectrometry (MS/MS) is used to analyse each blood sample and where there is a diagnosis, immediate treatment can begin to prevent serious disease later in life.
The study, published in Nature Medicine, aimed to compare the efficacy of whole-exome sequencing with that of MS/MS in identifying 48 rare metabolic disorders. Using historical DNA samples from 1334 babies born in California between July 2005 and December 2013, the research team predicted that exome sequencing may prove better than the current method given that the genetic basis of these conditions is well-characterised.
However, the team found that MS/MS screening identified 99 percent of babies with metabolic disorders with a false positive rate of just 0.2 percent compared to exome sequencing, which would have identified only 88 percent of positive cases but also resulted in 8000 babies each year erroneously considered to require urgent evaluation.
'All of the prior studies of utility of exome sequencing have started with a patient already in front of a doctor' said Dr Puck. 'When you switch to screening mode, you don't have any clues'.
A reason suggested for this discrepancy is that the complexity of the exome has been exacerbated by the diversity of California's population. This has led to the presence of genetic variants that have never been analysed before.
'These are well-studied single-gene conditions, but that does not mean we have found all the genes associated with them,' said first author Dr Aashish Adhikari. 'Additional genes could be involved, as well as additional biological and environmental factors that may limit our ability to predict disease from DNA sequences alone.'
However, the researchers still point to the use of exome sequencing, particularly when making a definitive diagnosis in cases where MS/MS identify a problem but doctors are unsure of diagnosis.
'If the current mass spectrometry testing comes out unclear, sequencing could reveal a gene variant that solves the mystery,' said Dr Steven Brenner, co-senior author of the study. 'Sequencing to screen additional carefully vetted disorders could enable timely treatment of some children with conditions that presently go unrecognised until it's too late for optimal intervention.'