Rapid Whole Genome Sequencing continues to provide answers and hope for parents of critically ill children with rare diseases

If a Major League Baseball player were to step up to the plate 150 times and get a hit 76 times, his batting average would be an unthinkably torrid .507. 

When it comes to identifying genetic causes for some of the rarest and serious diseases in children, CHOC has put up numbers that even Mike Trout couldn’t dream of achieving. 

Since July 2017, CHOC has ordered the comprehensive and cutting-edge test of rapid whole genome sequencing (rWGS) on 150 patients, with 76 of them getting a precise diagnosis that, in many cases, has resulted in life-changing care. 

“We took what could have been a diagnostic odyssey for these patients and families and cut it down from weeks, months, and sometimes years to, in some cases, only three days,” says CHOC pediatric intensive care unit medical director Dr. Jason Knight, part of an informal leadership team that oversees treatment of critically ill kids with rare diseases in the NICUPICU and CVICU. Other ICU physician team leaders include Dr. Adam SchwarzDr. Juliette Hunt and Dr. John Cleary

CHOC’s rWGS research program was championed by the late Dr. Nick Anas, CHOC’s former pediatrician-in-chief who was director of pediatric intensive care and a beloved figure at the hospital. Dr. Anas, who started at CHOC in 1984, died on April 3, 2018. 

Dr. Anas’ vision for the rWGS research program continues to be realized with successful patient outcomes, from the 2019 diagnosis of an infant girl with the extremely rare cardiac condition Timothy Syndrome to, more recently, a baby boy – Oliver Marley – with a genetic disorder that has been detected in only 10 children worldwide. 

“The CHOC team believed in Oliver – they loved him and took care of him and saw worth in him,” says Caroline Marley of her son, who turns 10 months old this May and was cared for by CHOC clinical teams during two stays, once in the NICU and the second time in the PICU. 

“They told me, ‘We want you to take your baby home,’” Caroline says. 

Testing began in 2017 

Each of us has some 22,000 genes in our bodies that dictate things ranging from the color of our hair to whether we are tall or short. Genes also produce the proteins that run everything in our bodies. Although individually rare, there are more than 6,200 single-gene diseases. RWGS is the technology that, with just a teaspoon of our blood, allows us to look at all the genes in our cells.  

At CHOC, rWGS testing became prominent with the launch of Project Baby Bear in fall 2018. CHOC was among five hospitals to participate in that program, led by Rady Children’s Institute for Genomic Medicine (RCIGM) in San Diego. RCIGM has a lab that runs sequencing. 

“To have (the RCIGM) close by and to be a close partner with them has been great,” Dr. Knight says. “We are way ahead of many other pediatric hospitals in this area. It’s a great success story, and something I’m really glad to be a part of.” 

A total of 45 CHOC patients got tested through Project Baby Bear, a $2-million state program for critically ill infants age 1 or younger who were enrolled in Medi-Cal. Of those 45 patients, 55.6 percent – 25 children – were able to have their rare diseases properly diagnosed, says Dr. Neda Zadeh, a CHOC medical geneticist who was involved with setting up CHOC’s rWGS program with Dr. Anas and who has seen most of the 150 kids tested thus far. 

CHOC actually began ordering rWGS testing on patients the year before in a partnership with RCIGM and Illumina, a leading developer and manufacturer of life science tools and integrated systems for large-scale analysis of genetic variation and function. In that 2017 program, 82 CHOC patients were tested with a 47.6 percent positive diagnosis rate, says Ofelia Vargas-Shiraishi, a senior clinical research coordinator in critical care/neonatology research at CHOC. 

CHOC has paid for an additional 23 children to undergo rWGS testing outside of the now-completed Ilumina and Project Baby Bear programs, and continues to have funding on a case-by-case basis, says Dr. Schwarz. 

“In the long run,” Dr. Schwarz says, “we’re saving money by avoiding expensive workups.” 

Adds Dr. Knight: “For a lot of these families, having an answer – even one they might not want to hear – is extremely important.” 

For parents like Caroline Marley, the results have been priceless. 

‘Wouldn’t place money on your son’ 

Oliver was born at 33 weeks after a complicated pregnancy for Caroline, who had a partial placental abruption when she was 14 weeks pregnant. Caroline and her husband, Ted, have another son, Charlie, 4, who is healthy. 

Oliver Marley with his older brother, 4-year-old Charlie

Born weighing 5 pounds and 4 ounces, Oliver had bruises over much of his body and had to be intubated a day after birth when he went into respiratory failure. Doctors detected a small brain bleed and noticed that, at 6 days old, both of his middle fingers were contracted. 

“I’ve never seen this before,” a neurologist at another hospital where Oliver was being treated told the Marleys. 

Oliver also had difficulty swallowing. He could move his arms and legs a bit, but he couldn’t open his eyes. 

Doctors suspected he might have muscular dystrophy. 

After other complications, doctors told the Marleys that Oliver’s outlook looked grim and that he may have to be sent to an acute-care facility. 

“We can’t help him,” one doctor told Caroline. “I don’t believe he will ever come home. If I were going to Vegas, I wouldn’t place money on your son.”  

It got to the point where the Marleys felt Oliver wasn’t getting the best care, so they decided to transfer him to CHOC. A nurse at another hospital whom the Marleys knew recommended CHOC.  

“We will absolutely take him,” a CHOC nurse told the Marleys. 

Oliver transferred to CHOC on Aug. 11, 2020. 

At 8 weeks old, Oliver underwent a tracheotomy and was attached to a ventilator. 

“He literally started thriving,” Caroline recalls. “He started growing because he was not working so hard to breathe. You could just see he was doing better.” 

Still without a diagnosis, Oliver went home on Oct. 19, 2020 with a tracheostomy tube and a ventilator.  

He returned to CHOC after he contracted a viral infection. 

Not convinced Oliver had muscular dystrophy, Dr. Schwarz suggested him as a candidate for rWGS.  

Three days later, in mid-November 2020, the Marleys received an answer: Oliver had two extremely rare genetic changes in his AHCY gene that potentially resulted in S-AdenosylHomocysteine Hydrolase (SAHH) deficiency.  

It is an extremely rare condition with less than 30 patients reported in the world and CHOC’s Dr. Richard Chang, a metabolic disorders specialist and  biochemical geneticist, was consulted to confirm the diagnosis. The disease, which affects brain, muscle and liver development, is associated with high blood levels of methionine and extremely high levels of toxic S-AdenosylHomocysteine (SAH) that interferes with vital cellular growth. 

Oliver was put on a delicate protein-restricted diet to limit the production of SAH without causing protein malnutrition, and his condition immediately improved. Other medications were added subsequently to provide nutrients that deficient due to the toxicity of SAH. He has a condition that is identical to a girl in Pennsylvania who was diagnosed at age 3 and later underwent a liver transplant. That girl is now 9. 

Oliver is scheduled to receive a liver transplant soon, Caroline says. 

Expanding access to rWGS testing 

A lawmaker in San Diego, in partnership with Rady Children’s Hospital and Health Center, is pushing for a new law that would expand access to rWGS testing by qualifying it as a Medi-Cal covered benefit for babies hospitalized in intensive care. 

Assembly Bill 114, The Rare Disease Sequencing for Critically Ill Infants Act, not only would expand availability of such testing to more families, but also would reduce state spending by eliminating many unneeded procedures, treatments and longer hospital stays, State Assemblyman Brian Maienschein wrote in a recent op-ed piece.  

“For critically ill infants hospitalized with unexplained rare diseases,” Maienschein wrote, “the opportunity to benefit from a medical miracle has arrived.” 

Caroline Marley sees that miracle daily with Oliver, who now is up to 20 pounds and moving around more. 

“We at CHOC are slowly building a case for early introduction of rWGS into the clinical management of these difficult cases in high-acuity settings to improve lifelong clinical outcomes and quality of life,” says Brent Dethlefs, executive director of the CHOC Research Institute. 

“There’s growing evidence that early introduction of this technology results in overall cost savings,” Brent adds. “It’s important to get more insurance carriers to cover the cost of this testing over time, which will make rapid whole genome sequencing more available to vulnerable and underserved populations. CHOC always has been an advocate for social justice in health care, which includes greater access to genomic testing.” 

Caroline Marley praises the entire collaborative team at CHOC and the entire CHOC Specialists Metabolic Disorders division, including Dr. Chang, who is in charge of maintaining Oliver’s health until transplant; Erum Naeem, clinical research coordinator, NICU; and Cathy Flores, clinical research nurse coordinator, critical care. 

“It was a team effort involving the critical care, neonatology, metabolic and genetics teams, just to name a few, and a very strong partnership with RCIGM,” says Ofelia Vargas-Shiraishi, a clinical research coordinator at CHOC. 

“We had everyone by our side every step of the way,” Caroline adds. “Child life was amazing, and so is the spiritual care team. If you’re willing to learn, they’re willing to teach you.” 

Dr. Zadeh says the success of CHOC’s rWGS program – with its whopping .507 batting average – is a result of “a very unique blend of the right people coming together at the right time and the right institution with the right set-up.” 

She adds, “I don’t think it would have worked necessarily at every hospital. I think CHOC is unique. We have the right group of kids we are testing. And we have the right group of specialists involved. 

“We love our families. We get to have really great relationships with them. This program just shows that CHOC is all about the whole care of the child and the family.” 

Rapid genome testing for infants saves lives, costs

Its name conjures up images of a familiar fairy tale, but Project Baby Bear has produced some very impressive real-world results that could save the lives of thousands of seriously ill infants.

The recently completed two-year pilot program at five clinical sites in California – including CHOC – helped doctors target a baby’s specific genetic disease in a matter of days, instead of the four to six weeks required for standard genetic tests.

That means quicker diagnoses leading to quicker treatments, less time in the hospital and more answers for anxious parents.

“It can be a real game changer,” said Dr. Jason Knight, a pediatric critical care physician and medical director of CHOC’s pediatric intensive care unit and one of the physician leads on the project. “It’s a tool we didn’t have a few years ago.”

Changing the game

By employing rapid whole genome sequencing (rWGS), doctors could gather vital information that changed the decisions families and clinicians made, and ultimately saved lives and resources. The procedure has historically been used only as a last resort.

By pinpointing the cause of rare disease with rWGS, physicians can customize treatment. And having a genetic diagnosis can eliminate the need for further tests, improve outcomes, reduce hospital stay length and improve the experience of care for families – all while also reducing costs.

In addition, substantial reductions in healthcare spending — $2.5 million — accrued largely because rWGS permitted doctors to discharge babies sooner and reduce the number of procedures that may have been performed in the absence of a precise diagnosis.

Avoided procedures included 11 major surgeries and 16 fewer diagnostic tests such as  open muscle, liver and other biopsies that are performed under general anesthesia.

Success story

In one case, a newborn baby girl with a life-threatening irregular heartbeat was admitted to CHOC Hospital. Instead of undergoing an arduous battery of tests, the child was diagnosed within two days with Timothy Syndrome, an extremely rare cardiac condition that put her at risk for sudden death.

With the genetic diagnosis in hand, CHOC physicians were able to treat the infant with the appropriate medication  for her condition. Her heartbeat was restored to normal, significantly reducing the risk of sudden cardiac death. Her physicians, secure in her diagnosis, implanted a pacemaker, dramatically improving her chances for a happy and healthy childhood.

She recently celebrated her first birthday.

“Without the results of her rapid whole genome sequence, she would have gone home on a different medication and been at a much higher risk for sudden death,” Dr. Knight said. “She got the right diagnosis and we gave her a pacemaker so her risk of sudden death went to zero.”

In all, Project Baby Bear provided diagnoses for 76 of the 178 babies who completed rWGS. This led to a change in the care of 66 babies. It diagnosed 35 rare conditions that occur in less than one in 1 million births. About 150,000 children could benefit from rWGS.

Turning every stone

Even if the test doesn’t diagnose a problem, it can help comfort families, Dr. Knight said.

“Even a negative test can be helpful for some families to know we’re not missing something,” he said. “It gives them assurance that we’ve turned over every stone.”

With the success of the study, Dr. Knight hopes to see the service expand to reach more patients.

“Should we be doing this with all newborns?” he asked. “Based on our experience with Project Baby Bear, it would seem feasible that for newborns and children in intensive care units without clear diagnoses, this should be part of our diagnostic process and the earlier the better.”

Multidisciplinary, multi-site effort

CHOC’s role in Project Baby Bear is a collaborative, multi-disciplinary effort involving many clinicians and staff, including research coordinators Cathy Flores, Erum Naeem and Ofelia Vargas-Shiraishi, and physician leads Drs. John Cleary, Juliette Hunt, Adam Schwarz and Neda Zadeh, in addition to Dr. Knight.

Led by Rady Children’s Hospital-San Diego, Project Baby Bear helps infants who are undergoing intensive care and covered by Medi-Cal. The other participating hospitals include UCSF Benioff Children’s Hospital Oakland, UC Davis Children’s Hospital in Sacramento, and Valley Children’s Healthcare in Madera.

The $2 million Project Baby Bear was funded by the State of California. In-kind contributions of $400,000 from Rady Children’s Hospital ensured more than 90 percent of the state funds were used to support the care and management of critically ill babies.

Learn more about the CHOC Research Institute.

CHOC to host NeoHeart: Cardiovascular Management of the Neonate Conference, March 27-29

Newborns with congenital heart disease are some of the most critical and fragile patients, says Dr. Amir Ashrafi, cardiac neonatologist at CHOC. To help address the needs of this complex patient population and their families, CHOC will once again be hosting NeoHeart: Cardiovascular Management of the Neonate. The conference will be held March 27-29, 2019 at the Hyatt Regency in Huntington Beach, and anticipated to attract over 650 attendees, from both across the country and internationally.

“It is imperative that physicians, nurses, and all front-line providers work closely together to give these babies the best chance at success” Dr. Ashrafi explains.

The dynamic, TED-style talk conference will emphasize cutting-edge science, innovations in medical care, controversies in management, as well as the importance of eliminating silos and creating an all-inclusive team which includes the families of neonatal patients. Physicians, physician’s assistants, nurses, nurse practitioners, fellows, residents, and other allied health professionals who specialize in neonatology, pediatric cardiology, pediatric intensive care, and cardiothoracic surgery are invited to attend.

Given the remarkable success of NeoHeart in previous years, Dr. Ashrafi, Dr. John Cleary, neonatologist at CHOC and colleagues from around the world launched the first international Neonatal Heart Society. The group works closely with other professional organizations including the American Academy of Pediatrics (AAP), World Congress of Cardiology, and Pediatric Cardiac Intensive Care Society to advocate for newborns with congenital heart disease and hemodynamic instabilities.

To register for NeoHeart: Cardiovascular Management of the Neonate, click here: www.choc.org/neoheart2019

This activity has been approved for AMA PRA Category 1 Credit TM