Pediatricians Leverage Genetic Testing for Faster Diagnoses

At Children’s Hospital Colorado, Aurora, Colorado, pediatricians will soon have a new ally in diagnosing and identifying complex neurodevelopmental conditions like epilepsy, attention-deficit/hyperactivity disorder (ADHD), and autism: Genetic testing.

Later this year, primary care clinicians and pediatricians at the health system will be able to initiate genetic testing for children with neurodevelopmental and other disorders directly through the electronic health record system. The goal is to make diagnosing genetic conditions and finding DNA variants more efficient.

“Pediatricians are busy. They are seeing lots of patients. They don’t have a lot of time,” said Scott Demarest, MD, a neurologist and medical director of the Precision Medicine Institute at the facility in Aurora, Colorado. “You have to think about how to make it easy on them, and I think we have the ability from a technology standpoint to start doing that more than we could in the past.”

The approach addresses a critical challenge in pediatric care: Helping busy primary care clinicians efficiently identify and manage neurodevelopmental conditions. At Children’s Hospital Colorado, an artificial intelligence algorithm will notify a clinician when genetic testing is recommended. Pediatricians then follow a checklist based on guidelines to order a test, reducing uncertainty, Demarest said.

Major medical centers and hospital systems across the country are opening precision medicine clinics, which tailor medical treatment to the individual characteristics of each patient, who may have rare genetic conditions or more common conditions like ADHD. These clinics utilize a range of specialists, from psychiatrists and social workers to neurologists and geneticists.

Despite established guidelines and benefits of genetic testing, the majority of children with neurodevelopmental disorders do not receive crucial genetic evaluations that could aid in diagnosis and unveil DNA variations that dramatically alter their treatment plans and quality of life.

Demarest and his colleagues in 2023 analyzed data from genetic testing of children with epilepsy at the health system. They found that between 2016 and 2020, the time from when a child first had a seizure to when they underwent testing decreased from 3 years to 8 months. The percentage of tests that successfully identified a genetic cause for their seizures remained roughly stable (11%-13% over the study period) despite a 292% increase in the average number of tests conducted per month. Over 75% of the genetic variants found to cause disease helped inform clinicians on treatment decisions, Demarest said.

Tomi Pastinen, MD, PhD, director of the Center for Pediatric Genomic Medicine at Children’s Mercy Kansas City in Kansas City, Missouri, spearheaded a similar approach in rural communities, providing primary care clinicians with direct access to genomic testing.

Direct-to-provider testing shortened the time to diagnosis by 5.5 months compared with the standard method of first referring patients to a specialist. For instance, genetic testing ordered by a primary care provider showed that the cause of autism and global developmental delay in one patient was caused by a pathogenic variant in a gene, ZNF462, known as Weiss-Kruszka syndrome, a rare condition with a prevalence estimated to be less than one in a million people.

“We’ve found that directly empowering primary care providers to order genetic tests can uncover undiagnosed genetic disorders in these underserved populations,” he said.

Implications for Care

A recent study underscores how genetic testing can change the trajectory of care for some of the estimated 8% of children and teens in the United States who have a neurodevelopmental disorder.

“There are a lot of patients who are out there that are alone, part of ultrarare communities that don’t have foundations, don’t have advocacy, don’t have anyone really looking into what the etiology of the condition is or how to even manage it,” said Julian Martinez-Agosto, MD, PhD, an associate professor of genetics at UCLA Health.

Martinez-Agosto and his team analyzed data from pediatric patients at UCLA’s CARING Clinic, a multidisciplinary clinic that opened in 2015 to evaluate and treat adults and children with neurodevelopmental disorders.

Of 246 patients who underwent genetic testing at the clinic, 41% had their care plan changed because of the finding of a genetic variant. Genetic testing led to actionable changes in clinical management including: Referrals to a specialty clinician (69.4%), cascade testing for the patient or their family (30.6%), medical surveillance (30.6%), genetic counseling (22.2%), medication changes (13.9%), and referral to a clinical trial (2.8%).

“We rarely had more than one case with the same genetic diagnosis. The vast majority of them had a unique genetic condition that we never saw again over many, many years,” Martinez-Agosto said.

The study findings underscore the need for more widespread adoption of genetic evaluations in pediatric care, Pastinen said. Testing results may explain developmental delays and prompt reproductive planning. Testing may also help uncover risks related to a patient’s condition, including cancer or cardiovascular complications, which have both been linked to autism spectrum disorder.

“Once we diagnose a genetic disorder in a family, it’s not just about managing the immediate patient’s condition,” Pastinen said. “It opens doors to identifying risks for siblings, addressing parents’ questions about recurrence, and pointing families toward the right specialty care.”

Genetic testing can also provide emotional relief for families.

“Many parents feel immense guilt, wondering if they’ve done something wrong,” said Pastinen. Receiving a genetic diagnosis often alleviates that burden and helps families plan for the future, including understanding recurrence risks for future pregnancies, he said.

Challenges

Experts say genomic-informed care has shown remarkable potential for children with neurodevelopmental and other disorders. However, the widespread adoption of genetic testing in pediatrics faces obstacles.

Parental hesitancy is a consideration, Martinez-Agosto said. Even when referrals for genetic testing are made, many parents do not follow through.

“There’s hesitancy in what that information might reveal. Hesitancy in how that information is handled, once it is obtained and what it is used for,” Martinez-Agosto said.

Demarest with Children’s Hospital Colorado said the health system recently started sending genetic kits with instructions for cheek swabs to families’ homes to minimize barriers to testing like taking time off work.

“When they have a lot of hoops to jump through, we lose patients along the way because they just can’t make all of it work,” said Demarest, adding the disproportionate impact on less-resourced families who may need to travel long distances for repeated and prolonged clinic visits.

Meanwhile, some primary care clinicians question the practical value of identifying ultrarare genetic conditions with no immediate therapeutic options.

“Our research aims to shift the mindset that genetics doesn’t impact care,” Martinez-Agosto said.

But some clinicians’ concerns are valid. For a majority of patients receiving a new diagnosis or a genetic variant through genetic testing, no effective therapy is available to treat the identified condition, said Pastinen.

Meanwhile, Demarest and his colleagues also observed an increase in genetic findings with uncertain significance. As a result, both physicians said insurers are overall hesitant to order or pay for a test that will not result in a specific therapy to treat the disease.

“So there’s kind of a narrow-sided view from the payer perspective that if [follow-up treatment] is the only kind of worthy outcome, it does not justify the cost of genetic testing,” Pastinen said.

Payers typically prioritize immediate therapeutic interventions, overlooking other outcomes of genetic testing, Martinez-Agosto said.

“Despite existing guidelines that have demonstrated clinical utility and the consensus that this testing should be part of medical care, insurance companies are very hesitant to jump in when new” genetic tests hit the market.

According to Pastinen, insurance is more likely to approve genetic testing if a referral comes from specialists such as neurologists.

The Post-Diagnosis Journey

As the prevalence of neurodevelopmental disorders grows among children, maintaining the same level of comprehensive care becomes increasingly challenging. To address this, the CARING Clinic developed a model that provides intensive initial support and then consultations with its own specialists.

“We see patients for a few visits,” Martinez-Agosto explained. “At the first visit, we gather all concerns and perform genetic testing. At the follow-up, we deliver results and create a management plan.”

Then, the clinic helps to transition many patients to primary and specialty care in their own communities.

“We empower those families to actually rely on the resources that they have in their community because some of our patients drive many hours to see us,” said Martinez-Agosto. “We want to make sure that in their community they have quick care that minimizes the barriers.”

The clinic’s specialists continue to remain accessible for patients, if they need it.

“The idea is to lessen the burden on the patient,” he said.

Demarest has consulted for, received grant funding from, and served on advisory boards of BioMarin, Neurogene, Marinus, the National Institutes of Health, and Mila’s Miracle Foundation. FamilieSCN2A, among others. The Precision Medicine Institute at Children’s Hospital Colorado has ongoing partnerships with Illumina, although Demarest reported not receiving any direct compensation from this partnership.

Martinez-Agosto, Pastinen reported no relevant disclosures.

Lara Salahi is a health journalist based in Boston.