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.” 

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Update from CHOC Physician-In-Chief, Dr. Nick Anas

I am very proud to be entering the new academic year as the recently named CHOC senior vice president and physician-in-chief (PIC). Our President and Chief Executive Officer (CEO) Kim Cripe sees this as a natural progression from the pediatrician-in-chief position I have held over the past several years. My primary objective remains to further CHOC’s clinical and academic vision. In this newly expanded capacity, I will continue my focus on nurturing relationships, both internally and externally, clinically and academically. I look forward to working with you all to create a brighter future for our patients and their families.

CHOC Physician-In-Chief, Dr. Nick Anas

I take great pride in the level of care we provide to our patients, and I am honored to have spent the vast majority of my career at CHOC. Even in my expanded role, I will not step entirely away from the privilege of caring for our patients and families. You will continue to see me in the PICU and CVICU on a fairly regular basis as I continue my research efforts, as well as on-going teaching and mentoring of our residents and fellows.

This will be another exciting academic year, as we enter a new chapter in the growth of world-class programs. We recently opened our new private-room NICU, and look forward to the 2018 opening of our mental health inpatient center. We will continue growing our fellowship programs, increasing our emphasis on collaborative relationships, and striving toward innovative population health management strategies. Within the next 30 days, the CHOC and Rady Children’s Institute for Genomic Medicine Research Collaborative will launch two exciting projects. We are also preparing to begin the recruitment of our first ever chief scientific officer (CSO). And finally, I am extremely encouraged by the growth in philanthropy here at CHOC, and look forward to participating in our Transformational Venture Funding and our numerous Innovation Institute initiatives.

While I can’t possibly list all the exciting projects and program advancements happening on our hospital campuses, I would like to again say how proud I am to be in a position to work with you as we continue our focus on excellence in clinical medicine, teaching, research and innovation at CHOC.

Nick Anas, MD

CHOC Physician-In-Chief 

News from CHOC Pediatrician-In-Chief, Dr. Nick Anas

I would like to wish you a very happy and healthy new year.  As we leap into 2017, I’d like to take a few moments to reflect on just a few of the milestones that were achieved at CHOC in 2016. Each year we raise the bar in providing the best care possible to the children and families that we serve, and 2016 was no exception. We added faculty and staff, launched several programs and services, broke ground on two new inpatient units, and made great strides in clinical research.

CHOC  Pediatrician-In-Chief, Dr. Nick Anas

Many of you are aware that CHOC was once again named a “Top Children’s Hospital” by the Leapfrog Group for providing the safest and highest quality services to our patients. This is a highly prestigious designation, as CHOC is one of only nine children’s hospitals in the nation and the only children’s hospital on the West Coast to receive this honor.

This distinction helps us to recruit the best and the brightest to CHOC, and in 2016, we welcomed nearly 40 new medical staff members representing 22 specialties. While this allows us to better serve Orange County families, we continue to treat patients traveling to CHOC from other counties, states and even countries, seeking our expertise through specialized programs such as our world class feeding, epilepsy/neurosciences, and orthopedic surgery programs, just to highlight a few. The Pediatric Subspecialty Faculty (PSF) and CHOC Specialists (CS) alone is now comprised of over 150 medical and surgical specialists.

In April, we opened our Adolescent and Young Adult (AYA) Cancer Unit within the Hyundai Cancer Institute. Our new AYA Unit provides an inpatient treatment setting designed to meet the needs of our adolescent and young adult patients. CHOC recently added oncologists specializing in the unique needs of adolescent and young adult patients.

In September, we formally broke ground on the CHOC Mental Health Inpatient Center. This will be an 18-bed mental health unit with outdoor recreation space, serving children from ages 3 through 18 years old. When this unit opens in early 2018, it will be the only inpatient program in Orange County serving children under the age of 12.

In 2016, we also began the build out of our state-of-the-art, expanded Neonatal Intensive Care Unit (NICU). Scheduled to open in the summer of 2017 on the fourth floor of the Bill Holmes Tower, the NICU will offer 37 rooms, of which 36 will be private, designed to allow parents to comfortably remain at the bedside while we care for their critically ill newborns. The new unit will also contain our recently expanded neurocritical services, offering increased capacity for whole body cooling and long-term video EEG monitoring for prevention and early detection of seizure activity in newborns.

We also expanded our outpatient adolescent/teen program, now located in the Centrum North Building. By adding services, offered by both male and female physicians specializing in adolescent medicine, CHOC is able to better meet the unique needs of our teenage patients.

In 2016, CHOC clinicians published more than 330 manuscripts and delivered more than 200 lectures. The CHOC Research Institute had 369 active IRB-approved clinical research studies across multiple specialties. A prime example of our emphasis in research is the recruitment of Dr. Jeff Huang, a PhD scientist, who is partnering with Dr. Raymond Wang, a physician scientist. Together, they hope to advance the understanding of Pompe Disease. Through our partnership with UC Irvine and the Institute for Clinical and Translational Science, we awarded five promising pilot research grants. And the Hoag Foundation awarded CHOC Principal Investigator Phil Schwartz, PhD with a three-year $1,048,168 grant to advance pediatric stem cell research with the goal of filing a “Pre-Investigational New Drug” application with the FDA.

The Sharon Disney Lund Medical Intelligence and Innovation Institute (MI3) at CHOC continues to grow, advancing the culture of innovation and supporting thought leaders from around the world to join together in pursuit of innovative approaches to improve the lives of children. This year, MI3 launched the first innovation education/training program at CHOC, which included an innovation challenge. The first place challenge winners were invited to present at the International Peds2040 Conference in Miami this month. Institute director, Anthony Chang, MD, leads with the philosophy that “The best and fastest way to innovate, is to collaborate.” The result of this philosophy was the creation of The International Society for Pediatric Leadership (iSPI), now comprised of 33 children’s hospital members (and growing). Last summer, nearly 100 future healthcare innovators participated in MI3’s Intern Program.  Also in 2016, Dr. Chang became the president of the OC/SD Chapter of the Society of Physician Entrepreneurs (SoPE). To close a successful year, MI3 hosted the AIMed Conference in December, with over 400 participants.

And finally, this year CHOC launched our refreshed 2020 Strategic Plan, which will serve to guide us in 2017 and beyond as we continue to reach new goals in expansion and enhancement of patient care. One of the major initiatives in the strategic plan is our population health strategy. With the creation of the CHOC Network, we are taking transformative steps toward seamless integration of specialty and primary care providers, with primary care as an increasingly important part of the continuum of care. As one of only 29 healthcare recipients nationwide and the only pediatric institution, CHOC received a four-year Center for Medicare and Medicaid Innovation (CMMI) Transforming Clinical Practice Initiative Grant totaling $17.8 million. Working in partnership with Rady Children’s Hospital, we are launching new care model designs across the care continuum for enhanced coordination of inpatient, primary, emergency, urgent care and specialty care services.

While I wish that I could list all of our accomplishments from calendar year 2016, it is simply not possible, as there are far too many to mention here. Suffice it to say, we should all be very proud. With everything else going on in the world around us, we can say that we continue to focus on the health and well-being of the children and families that we serve, providing expanded, higher quality care, setting the stage for a great 2017. I would like to congratulate you all on a job well done. The future at CHOC is bright!

Here’s to a happy and healthy 2017.

Nick Anas, MD

CHOC Pediatrician-In-Chief 

Drs. Nick Anas and Mitchell Katz Discuss Success of CHOC’s Clinical Leadership Council  

Dr. Nick Anas, CHOC’s pediatrician-in-chief, sat down with Dr. Mitchell Katz, director of CHOC’s Multidisciplinary Feeding Program and pediatric GI lab services, to talk about CHOC’s Clinical Leadership Council (CLC), and how it has benefited programs like the feeding program.

CHOC’s Multidisciplinary Feeding Program is one of a few specialty feeding programs in the country to offer comprehensive outpatient consultation and inpatient programs. With the support and success of CLC’s process, the feeding program has grown tremendously and increased the number of patients it can treat.

Watch this brief video to learn more about CLC and the feeding program.