Could whole-exome sequencing become a standard part of state newborn screening?

smiling baby boy

There are concerns about implementing whole-exome sequencing since it takes away the child’s right to decide if they want to know — or not — about their specific inherited disease.

It is still premature to standardize an innovative methodology known as whole-exome sequencing (WES) as part of state newborn screening programs, argues Beth A. Tarini, M.D., M.S., associate director for the Center of Translational Research at Children’s National Hospital, in a new editorial published in JAMA Pediatrics.

About 4 million infants are born annually in the United States. Newborn screening is a mandatory state-run public health program that screens infants for inherited diseases in the first days of life so they can receive treatment before irreversible damage occurs. Several of these screening tests are done on blood drawn from an infant’s heel.

WES holds the potential to screen infants for thousands of disorders and traits, including those that appear in adulthood. But there are concerns about implementing WES since it takes away the child’s right to decide if they want to know — or not — about their specific inherited disease. There is also the unknown effect that it could have on their ability to obtain health insurance.

“As caretakers for their children, parents have the challenge of deciding what kind of information, including genetic, will be valuable for their child,” says Dr. Tarini. “As a society, we have the responsibility of deciding where the healthcare dollars get the best return – especially when it comes to children. We need to start that conversation for universal genomic sequencing of newborns sooner rather than later.”

The Pereira et al. study, appearing in the new edition of JAMA Pediatrics and referenced in Dr. Tarini’s editorial, is the first to demonstrate no significant harm in the initial 10 months of life after performing WES under the best conditions of access to resources and a controlled environment.

While the Pereira et al. study has limited data on the effects of WES on families from underrepresented backgrounds, Dr. Tarini notes that it does provide a critical first step in this area of pediatric genomic research and for policy decision-making about the widespread implementation of WES in newborns.

“Moving forward, the U.S. will have to make a collective decision about the value of WES for newborns,” says Dr. Tarini. That value calculus cannot be made without consideration of the general state of healthcare for infants. As she points out, “This is not an easy question to answer in a country whose infant mortality ranks 34th according to the Organization for Economic Co-operation and Development (OECD).”

Dr. Tarini’s research identifies ways to optimize the delivery of genetic services to families and children, particularly newborn screening. She has also chaired state newborn screening committees and served on several federal newborn screening committees.

Ugandan boy in hospital bed

Acute rheumatic fever often goes undiagnosed in sub-Saharan Africa

Ugandan boy in hospital bed

Despite low numbers of documented acute rheumatic fever cases in sub-Saharan Africa, the region continues to show some of the highest numbers of people with, and dying from, rheumatic heart disease, the serious heart damage caused by repeat instances of rheumatic fever.

Despite low numbers of documented acute rheumatic fever cases in sub-Saharan Africa, the region continues to show some of the highest numbers of people with, and dying from, rheumatic heart disease, the serious heart damage caused by repeat instances of rheumatic fever. A population-based study in the Lancet Global Health collected evidence of acute rheumatic fever in two areas of Uganda, providing the first quantifiable evidence in decades that the disease continues to take a deadly toll on the region’s people.

“These findings matter. Access to life-saving heart surgery is only available to a very small fraction of the hundreds of thousands of patients in Africa who have irreversible heart damage from rheumatic heart disease,” says Craig Sable, M.D., associate chief of Cardiology at Children’s National Hospital and one of the senior authors of the study. “It’s time to focus upstream on capturing these conditions sooner, even in low-resource settings, so we can implement life-sustaining and cost-saving preventive treatments that can prevent further heart damage.”

The authors, who hail from Uganda and several institutions around the United States, including Children’s National and Cincinnati Children’s Hospital Medical Center, note this is the first study to use an active case-finding strategy for diagnosing acute rheumatic fever. They also note that raising awareness in the community and among its healthcare workers while also finding new ways to overcome some of the diagnostic challenges in these low-resource settings greatly improved diagnosis and treatment of the condition.

The study also described clinical characteristics of children ages 5 to 14 presenting with both definitive and possible acute rheumatic fever, providing further clinical data points to help healthcare workers in these communities differentiate between this common infection and some of the other frequently diagnosed conditions in the region.

“With this study, we can now confidently dismiss the myth that acute rheumatic fever is rare in Africa,” the authors write. “It exists at elevated rates in low-resource settings such as Uganda, even though routine diagnosis remains uncommon. While these incidence data have likely underestimated the cases of acute rheumatic fever in two districts in Uganda, they show that opportunity exists to improve community sensitization and healthcare worker training to increase awareness of acute rheumatic fever. Ultimately this leads to diagnosing more children with the condition before they develop rheumatic heart disease, so that they can be offered secondary prophylaxis with penicillin.”

Children with suspected acute rheumatic fever participated in this population-based study. Data was collected over 12 months in Lira district (January 2018 to December 2018) and over nine months (June 2019 to February 2020) in Mbarara district.

Follow-up of children diagnosed in this study will provide more data on the outcomes of acute rheumatic fever, including a better understanding of the risk for a child to develop rheumatic heart disease.

This work was funded by the American Heart Association Children’s Strategically Focused Research Network Grant #17SFRN33670607 and by DEL‐15‐011 to THRiVE‐2 and General Electric.

Learn more about the challenges of rheumatic heart disease in sub-Saharan Africa and other developing parts of the world through the Rheumatic Heart Disease microdocumentary series:


Spectral data shine light on placenta

preemie baby

A research project led by Subechhya Pradhan, Ph.D., aims to shed light on metabolism of the placenta, a poorly understood organ, and characterize early biomarkers of fetal congenital heart disease.

The placenta serves as an essential intermediary between a pregnant mother and her developing fetus, transporting in life-sustaining oxygen and nutrients, ferrying out waste and serving as interim lungs, kidneys and liver as those vital organs develop in utero.

While the placenta plays a vital role in supporting normal pregnancies, it remains largely a black box to science. A research project led by Subechhya Pradhan, Ph.D., and partially funded by a Clinical and Translational Science Institute Research Award aims to shed light on placenta metabolism and characterize possible early biomarkers of impaired placental function in fetal congenital heart disease (CHD), the most common type of birth defect.

“There is a huge information void,” says Pradhan, a research faculty member of the Developing Brain Research Laboratory at Children’s National Health System. “Right now, we do not have very much information about placenta metabolism in vivo. This would be one of the first steps to understand what is actually going on in the placenta at a biochemical level as pregnancies progress.”

The project Pradhan leads will look at the placentas of 30 women in the second and third trimesters of healthy, uncomplicated pregnancies and will compare them with placentas of 30 pregnant women whose fetuses have been diagnosed with CHD. As volunteers for a different study, the women are already undergoing magnetic resonance imaging, which takes detailed images of the placenta’s structure and architecture. The magnetic resonance spectroscopy scans that Pradhan will review show the unique chemical fingerprints of key metabolites: Choline, lipids and lactate.

Choline, a nutrient the body needs to preserve cellular structural integrity, is a marker of cell membrane turnover. Fetuses with CHD have higher concentrations of lactate in the brain, a telltale sign of a shortage of oxygen. Pradhan’s working hypothesis is that there may be differing lipid profiles and lactate levels in the placenta in pregnancies complicated by CHD.  The research team will extract those metabolite concentrations from the spectral scans to describe how they evolve in both groups of pregnant women.

“While babies born with CHD can undergo surgery as early as the first few days (or sometimes hours) of life to correct their hearts, unfortunately, we still see a high prevalence of neurodevelopmental impairments in infants with CHD. This suggests that neurological dysfunctional may have its origin in fetal life,” Pradhan says.

Having an earlier idea of which fetuses with CHD are most vulnerable has the potential to pinpoint which pregnancies need more oversight and earlier intervention.

Placenta spectral data traditionally have been difficult to acquire because the pregnant mother moves as does the fetus, she adds. During the three-minute scans, the research team will try to limit excess movement using a technique called respiratory gating, which tells the machine to synchronize image acquisition so it occurs in rhythm with the women’s breathing.