It's an 'edge-of-your-seat' story: The newborn's heart had stopped multiple times in the hours since her birth. Her doctors at Lucile Packard Children's Hospital Stanford had tried everything to help her, but her situation was dire.
The baby had an unusually severe form of an inherited cardiac condition called long QT syndrome. The syndrome, which is most often diagnosed in older children or adults, can be caused by a mutation in any of several genes; until the doctors knew exactly which genetic mutation was causing the condition they wouldn't know what drug would be most likely to help. The stakes were high: by her second day of life she'd received an implantable defibrillator and several intravenous drug infusions.
As cardiologist Euan Ashley, MD, PhD, explained to me:
The team literally tried everything we could think of to help this child, including trying every drug that could possibly make a difference. It was a heroic effort by a very diverse group of professionals.
The clinicians and researchers, including pediatric cardiologist Scott Ceresnak, MD, who managed the baby's clinical care, realized it was critically important to identify the baby's disease-causing mutation to learn which drug would be best for her. To do so, they dropped everything else they were doing and sequenced her entire genome to pinpoint the culprit within just ten days - an unprecedented feat. Ashley, who directs Stanford's new Clinical Genomics Service as well as its Center for Inherited Cardiovascular Disease, and pediatric cardiology fellow James Priest, MD, recently published the case study in the journal Heart Rhythm.
This is the future of genetic testing and we hope, the future of medicine.
Using customized commercial software and tools developed at Stanford, the researchers were able to zero in on a mutation in a gene called KCNH2 known to be associated with long QT. They also found another, novel mutation in a gene involved in determining the structure of the heart during development.
As Priest explained in an e-mail to me:
Whether it is a CT scan, x-ray, or genetic test, we work hard to make a diagnosis as quickly as possible when there is a critically-ill baby under our care. Whole genome sequencing returned this diagnosis in days instead of weeks. We were able to turn the raw sequence data into a diagnosis in about 12 hours.
In the case of an infant like this, the difference in turnaround between two months and two days could be the difference between life and death. This may be the fastest a whole-genome sequencing result has ever been directly integrated into a patient's acute clinical care.
The presence of the second mutation would not have been determined if the researchers had only looked for known long QT mutations (a more-targeted sequencing approach conducted on a panel of just a few genes known to be involved in the disease in question). As Priest described:
Looking within this baby’s genome there are many millions more pieces of information other than just the diagnosis. When we took a more broad view, we found a mutation in a second gene, which we believe could contribute to this baby’s long QT syndrome. Not only can we make a diagnosis when we do whole genome sequencing, but with a trained eye we can learn even more about a particular disease.
It's possible that the double-whammy of the two mutations is responsible for the severity of the baby's condition. However, based on the sequence, the care team was able to start the infant on gene-specific drug therapy much sooner than the weeks or months it would have taken with standard genetic testing, and she was discharged shortly after. According to Ashley:
It’s a new world. A test that normally takes two months can be turned around over a weekend, so the results can be given to the treating team to properly define the disease and personalize the care of an infant with a potentially lethal condition. This is the future of genetic testing and we hope, the future of medicine.
Previously Whole genome sequencing: the known knowns and the unknown unknowns, Assessing the challenges and opportunities when bringing whole-genome sequencing to the bedside and Stanford researchers work to translate genetic discoveries into widespread personalized medicine
Photo by Simon Powell