Disease Detectives: On a Mission for Answers to the Undiagnosable

After a difficult pregnancy, Mary Elizabeth and Meade Stone were thrilled to deliver identical twin boys, John and Warren. Their joy turned to shock the next day when John’s lips turned blue during a diaper change.

What followed was a plunge into a world of seizures, ventilators, urgent diagnoses and medical terms the couple never wanted to know. Both babies had too many seizures to count.

Despite the seizures, the babies’ screening tests were normal, including the epilepsy panel. The seizures affected both boys, so doctors assumed the cause may be genetic, but they didn’t have a specific diagnosis. “When you’re struggling with the fact that things aren’t going as expected, it adds to the suffering when you can’t put a name to the problem or wrap your mind around it,” says Mary Elizabeth Stone.

At 19 days old, baby Warren died from a tragic medical error at the Virginia hospital where the boys were born. The couple poured their grief and energy into finding answers and treatment for John.

It was three years before they finally received an answer, thanks to the disease detective work of ecxperts like Pankaj Agrawal, M.D., MMSc, chief of neonatology at the University of Miami Miller School of Medicine’s Department of Pediatrics and physician-in-chief at Holtz Children’s Hospital, Jackson Health System.

Pediatric diseases are rare, but having one is not.

One in 10 patients in the world has a rare disease, which is a disease that affects fewer than 200,000 Americans. While the diseases themselves are rare, having a rare disease is not. An estimated 25-30 million Americans have a rare disease. Most are ultra-rare, with only 10-50 cases in the country.

Rare diseases can have an underlying genetic cause, but the exact genetic disease is often unknown due to a lack of advanced genetic testing or knowledge. Parents desperate for answers turn to Dr. Agrawal’s laboratory as a last hope for a diagnosis. “We’re trying to understand the underlying mechanism of a disease. Without knowing the genetic cause, we can never find treatments,” says Dr. Agrawal.

Although some rare disorders, like Huntington’s disease, are seen in adults, the majority of the rare disorders affect children.

Disease detective research at UHealth

For over two decades, Dr. Agrawal has dedicated his research to becoming a leading world expert in disease detection. Dr. Agrawal previously built a center in Boston and is now building a Center for Orphan Disease (CODe) at UHealth.

His determination to identify causes of extremely rare pediatric diseases and find treatments has helped his team become known worldwide as “disease detectives.” They’ve discovered more than 50 novel genes. “We often identify a completely new condition caused by a gene that hasn’t been linked to a human disease previously,” says Dr. Agrawal.

The Stone twins, who were diagnosed with Ohtahara syndrome based on EEG findings — a type of seizure disorder — were the first-ever individuals described to carry mutations in the SCN2A gene. This gene had previously been linked to other forms of epilepsy and can present with symptoms resembling cerebral palsy. John passed away from complications of the disease at age 14.

Helping families worldwide

Families worldwide, from Israel and Uruguay to Florida and Boston, learn about Dr. Agrawal’s disease detective work and reach out as a last desperate cry for help. “Once you see the benefits the families experience from this approach, it just feels so special that your work is making a real difference,” says Dr. Agrawal.

Dr. Agrawal’s team enrolls children with undiagnosed conditions into a study to find the cause of the disease. They use whole-genome sequencing as the first step, which allows scientists to read every single letter in a patient’s DNA– the body’s instruction manual.

They look for any “typos” or mutations causing a health problem. Unlike screening tests that look at a few specific genes, whole genome sequencing gives scientists the full picture.

“We have a very specialized team with expertise to find a needle in the haystack. We find the cause in about a third of the cases,” says Dr. Agrawal.

In addition to genome sequencing, they use other multiomic approaches, including RNA sequencing and protein studies, as well as cellular and, if needed, animal modeling, to help find answers.

How UHealth’s physician-scientists diagnose rare diseases

When patients like John have symptoms that can’t be traced back to any known diagnosis, Dr. Agrawal’s team does deep and lengthy investigations to find answers. Here’s how the process works:

Patient enrollment and genome sequencing

The child with an undiagnosed condition and their family are enrolled in the CODe research study. The team uses whole-genome sequencing to search for genetic clues that might explain the child’s illness.

Deep dive into a patient’s medical history

Researchers dive into the child’s symptoms, medical history and lab results, building a detailed story that helps narrow down possible genetic causes.

Family and extended relative analysis

They examine the genetic data of parents, siblings and even extended family to identify inherited patterns and uncover hidden variants that may contribute to the condition.

RNA sequencing and protein studies

To see how the DNA mutations affect the body, the scientists sequence RNA (the step between DNA and proteins) to determine which genes are actually turned “on” or “off.” They may also study protein levels, structure or function to understand how a mutation impacts the body at a molecular level.

Model development

If the team identifies a suspect gene, they develop cellular or animal models to replicate the mutation. These models help the researchers understand how the gene functions and how it might be failing.

Global collaboration

The team contacts international research networks to find other patients with the same gene mutation. More samples can help the team determine how the mutation causes disease and potentially how it might be treated.

This process can take six months to many years. “It’s a long journey for every family and gene, but it’s very exciting to know what your child is suffering from so that we can find future treatments,” says Dr. Agrawal.

In some cases, the mystery remains unsolved, but Dr. Agrawal’s team perseveres. For years, the Stones didn’t know the cause of their twins’ disease. “I made some peace and accepted that we may never know because a lot of families still don’t have answers, but Dr. Agrawal’s team didn’t give up,” says Stone.

Diagnosis offers hope for treatment.

Having an answer and name for what’s causing your child’s disease offers tremendous relief, but the real goal is to find treatment. For the most fortunate, this can simply be a vitamin or medication. “There are some seizure disorders where the only thing you need is some extra enzyme available over the counter, like biotin or riboflavin,” says Dr. Agrawal.

For others, treatment is more complicated.

In a recent medical breakthrough, doctors treated a baby’s rare pediatric disease with a gene-editing therapy tailored to repair his specific mutation. This marked the first time doctors customized the use of CRISPR technology to fix a tiny, critical error in an individual patient’s genetic code.

The study published in May 2025 offers hope for other families like the Stones, whose children’s diseases are too rare for pharmaceutical investment.

Even for those cases with no existing treatment, simply having a diagnosis brings relief.

“Sometimes parents blame themselves for something they did during pregnancy, or if the family wants to have more kids, they can use this information to decide what to do,” says Dr. Agrawal.

That was the case for the Stones, who learned their sons’ diagnosis was unlikely to recur. They confidently had three more healthy kids, trusting they would not have to suffer in the way their brothers did. For John, having a diagnosis meant his doctors could select the most appropriate epilepsy drug for him.

The twins’ diagnosis from Dr. Agrawal’s team also helps hundreds of other families. The gene SCN2A is now part of the epilepsy panel. There’s a Facebook group of families whose kids have the genetic mutation, and there’s an RNA-based clinical trial in place to treat this gene mutation.

Mary Elizabeth Stone encourages parents of kids with undiagnosed diseases to never give up and seek the help of Dr. Agrawal’s team. “I’ve seen a lot happen in John’s lifetime. It wasn’t the right timing for him for a cure, but he and his brother have been a part of this scientific advancement that continues,” she says.

As a mother, Stone has always known her boys and their story matters. “I’m proud to know their hardships weren’t in vain. These talented and compassionate doctors were able to figure out their diagnosis so that it can be used to help other affected individuals going forward.”

Click here to learn more about the Agrawal Lab.

Written by Wendy Margolin.

Tags: Children's health innovations, Disease detection strategies, Dr. Pankaj Agrawal, Genetic disease diagnosis, Rare disease research