The standard treatment is a liver transplant, but this entails a high risk of complications in infants. Thanks to advances in gene sequencing and editing, however, doctors at the Children’s Hospital of Philadelphia and University of Pennsylvania’s medical school were able to custom-design and manufacture a substitute gene that was delivered to KJ’s liver via a lipid nanoparticle—a microscopic fat-based shipping container. Physicians announced in May that the treatment was successful, and KJ is thriving.
The episode highlights how rapid genetic sequencing and cutting-edge therapies could enable tens of thousands of babies born every year with rare and debilitating diseases to grow up normally. “The earlier we can diagnose, the earlier we give these families a chance for them to live a better life,” Katherine Stueland, CEO of GeneDx, says in an interview at the Journal’s offices.
GeneDx was founded in 2000 by two former National Institutes of Health scientists, Sherri Bale and John Compton. Many academic labs and genetic startups founded around that time sought to decode genes behind more common diseases. But rare diseases were neglected because there wasn’t believed to be much commercial upside in diagnosing them.
Sequencing a genome two decades ago cost more than a Beverly Hills mansion, and how much demand could there be to diagnose diseases that by definition are rare? Turns out, a lot. As sequencing costs have plunged, GeneDx has the potential to revolutionize the field of rare diseases—which, collectively, are more common than most people realize.
The Food and Drug Administration estimates that some 30 million Americans suffer from rare diseases. Many are never diagnosed, and GeneDx aims to change that. It sequences DNA for mutations that are responsible for thousands of disorders.
A single deletion or duplication in the genetic code can result in misshapen or missing proteins that are vital to a variety of physiological processes. A case in point: Duchenne muscular dystrophy can result from a mutation or deletion in any of the 79 protein-encoding genes that together produce the dystrophin protein, which stabilizes muscles.
Standard newborn screenings can identify a few dozen of the most common congenital disorders, such as cystic fibrosis and sickle cell disease. But “about 95% of the conditions that we’re diagnosing would be completely missed based on newborn screening standards today,” Ms. Stueland says.
GeneDx can diagnose more than 4,800 disorders caused by genetic mutations that either are inherited from parents or arise spontaneously. The company has sequenced the DNA of more than 850,000 individuals, which has enabled it to discover more links between gene variants and conditions. It now uses AI to connect the dots between diseases and genes.
“We’re making new gene disease discoveries now on a weekly basis,” Ms. Stueland, 49, says. “So we thought there were 7,000 rare diseases, but it turns out there are 10,000.” Most are caused by a single gene mutation, which means they could potentially be treated with gene-editing technologies, as KJ Muldoon was. Hundreds of gene therapies for rare disorders are undergoing clinical trials. Several await FDA approval, including treatments for Hunter and Wiskott-Aldrich syndromes. They cause enlarged organs and immune dysfunction, among other debilitating symptoms.
While not a medical doctor or geneticist, Ms. Stueland developed an interest in rare diseases when her cousins were diagnosed with cystic fibrosis. She recalls organizing a neighborhood raffle to raise money for the Cystic Fibrosis Foundation. The grand prize? Free baby-sitting. She graduated with a bachelor’s degree in English literature from Miami University where she performed in dance theater and later worked at small genetic diagnostic and biotech companies before being named CEO of GeneDx in 2021. This background enables her to blend the human element with the science.
While scientists know that some gene mutations cause certain disorders, there are also “variants of unknown significance,” Ms. Stueland says. That means scientists don’t know whether they are connected to a condition. But the more genomes GeneDx sequences, the more it can “upgrade or downgrade” a variant’s significance.
There are also gene variants that heighten the risk for disorders but not to 100%. “There are 800 genes associated with autism,” Ms. Stueland says. It isn’t well-understood how autism is affected by each of these genes, but sequencing more individual genomes can yield clues. Gene therapies might even be able to help some people with autism.
“I just heard from a family who had a young man in his early 20s that suspected that he had some form of autism his entire life,” Ms. Stueland says. “He actually had been adopted. And because we were able to diagnose him in his early 20s, there’s actually a company based in Chicago that has a gene therapy that is in clinical development that he would be eligible for.”
The company is Jaguar Gene Therapy, which is conducting a trial for autistic patients with a mutation or deletion in the SHANK3 gene. By enabling the rapid diagnoses of more rare diseases, Ms. Stueland hopes to help more patients access treatments and clinical trials.
About one-third of babies in neonatal intensive-care units have a genetic disorder, but very few of them receive a genetic test. Many of them have mutations that could be identified by GeneDx’s screening and benefit from prompt treatment. Its genome-sequencing is being used in a large-scale study backed by the New York State Health Department, in which every baby born in the New York Presbyterian hospital system is eligible to participate. Babies are screened for more than 450 “clinically actionable conditions”—those that could benefit from immediate interventions. That could mean a ketogenic diet, a beta blocker or another FDA-approved therapy, among other things.
Ms. Stueland’s hope is that as drug discovery progresses, more conditions will become “clinically actionable.” But she says GeneDx doesn’t want to give parents information about potential health risks that can’t be remedied: “No parent needs to hear that their happy healthy baby may have prostate cancer in the future.”
Parents who participate in the New York study are contacted by doctors with the results, usually within three to six weeks. The study has found a 3.7% positive rate in the first 4,000 babies. That means more than 3 in 100 have a genetic disorder that could be amenable to treatment: “We’re diagnosing disease at the earliest moment—sometimes before symptoms are fully manifesting.”
Consider rare inherited heart arrhythmias, which are responsible for nearly 20% of sudden infant death syndrome cases. Arrhythmias can be managed with beta blockers and heart monitoring. About a quarter of childhood seizures are caused by faulty genes. Identifying the responsible gene variant can help doctors determine an appropriate treatment.
Lili Hasse’s infant daughter, Margot, was diagnosed as part of the New York study with CDKL5 deficiency disorder, which causes seizures and delayed neuro-development. Ms. Hasse says Margot’s rapid diagnosis enabled her to schedule an appointment immediately with a pediatric neurologist who specializes in the condition and to connect with a support group on Facebook.
She considers herself lucky. Other parents in the group have run a yearslong medical gauntlet before their children were ultimately diagnosed. Thanks to medications, supplements, a ketogenic diet and physical therapy, “Margot has near complete seizure control,” Ms. Hasse says. Gene therapies in the pharmaceutical pipeline may also someday help Margot.
Parents of children with rare diseases are often extremely entrepreneurial and engaged, Ms. Stueland says. Some are “searching for an investigational compound that might help their child, or if not for their child, somebody else’s child in the future.”
The journal Nature this summer profiled parents of children with rare diseases who launched therapeutic startups. Some had business backgrounds, but few had any formal scientific training. Rare-disease startups like Ultragenyx and Alexion sponsor a Rare Bootcamp for parents seeking to develop rare-disease drugs for their children. Expanded genetic sequencing could enable such startups to recruit more patients for clinical trials.
Ms. Stueland says that a “chicken and egg” problem has long hindered development of treatments for rare diseases: “You need to have a diagnosis in order to motivate somebody to go find a treatment.” She hopes more states will expand access to genetic sequencing, as Florida has recently done.
Gov. Ron DeSantis in June signed the Sunshine Genetics Act, which passed the Legislature unanimously. It will allow parents to have their baby’s genetic code screened at no cost. Adam Anderson, the legislation’s sponsor, had a son who died at 4 from Tay-Sachs disease, a rare inherited syndrome that results in the death of nerve cells in the brain and spinal cord.
Ms. Stueland argues that expanding access to newborn gene screening could save the health system money by reducing the amount that is currently spent on other tests, scans and specialists to diagnose a disorder. Treating patients with rare diseases early could also forestall disease progression and prevent expensive hospital visits.
How much does a test cost? She says GeneDx gets about $3,700 for each test and its gross margins are around 80%, suggesting it costs the company around $750 to run the test. Its overall margins, however, are small—about $7 million on $302 million in revenue last year—because it pumps a lot of money into improving its technology and scale.
She’s confident the cost of testing will continue to decline while benefits from new discoveries grow. That has been the history. The first human genome took 13 years to sequence, wasn’t complete until 2003, and cost about $3 billion. “We can now interpret a whole genome in 48 hours,” she says. She credits the progress in part to a 2013 Supreme Court decision, Association for Molecular Pathology v. Myriad Genetics, which held that natural fragments of DNA couldn’t be patented. “That opened up the entire industry.”
The most prominent gene-sequencing company was 23andMe, which pitched DNA tests directly to consumers. Using only a small amount of saliva, the company claimed it could tell you about your ancestry and health proclivities, such as natural wake-up time or whether you’re more likely to excel at endurance sports or activities that require short bursts of power.
After a meteoric rise, the company flamed out and filed for bankruptcy in January. What are the lessons of its failure? “Where they really provided a change for the better was getting people curious about their genes,” Ms. Stueland says. But after shelling out hundreds of dollars for the kits, most of 23andMe’s 15 million customers weren’t willing to pay more for additional health insights of marginal value. The business model failed, she thinks, because it didn’t give healthy adults a way to use their genetic information proactively.
Ms. Stueland says she ultimately hopes to furnish information from GeneDx’s newborn screenings to the patients when they come of age, empowering them to make decisions: “Ultimately, your DNA is your DNA, and so if you want that information, we want to be able to provide it to you.”
But the central focus is helping children like KJ Muldoon and their parents. “Its examples like that,” she says, that “should give us all hope as a society, as an industry, as a country.”
Ms. Finley is a member of the Journal’s editorial board.