Mimi C. Lee, MD, PhD, outlines why genomic sequencing remains a powerful but carefully targeted tool in pediatric medicine today, as advancements continue.
As comprehensive genomic testing becomes more accessible in clinical practice, Mimi C. Lee, MD, PhD, Chief of Precision Genetic Medicine at GeneDx, discussed how advances in genomic knowledge are reshaping diagnostic decision-making—particularly for children with unexplained or rare conditions.
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Lee emphasized the sheer scale and complexity of genetic variation now recognized. “There are at least 10,000 different variants, depending on which database you look at,” she said, noting that some databases now report more than 16,000 variants. As genomic science evolves, researchers are increasingly able to connect specific variants to diseases that were previously difficult to characterize.
She cited both well-known and ultra-rare conditions as examples. Hemophilia, Lee explained, is caused by many different variants within a very large gene, while Duchenne muscular dystrophy also involves numerous pathogenic variations. “There are conditions that are super rare, like Rett syndrome, which affects girls,” she said, adding that specific variants—such as SHANK3 mutations—have been linked to certain forms of autism. Identifying these variants has allowed clinicians to pinpoint root causes using objective genomic data rather than relying solely on symptoms.
A central challenge, Lee noted, is determining when sequencing should occur. “The way I was trained and the way I practiced for 30 years, we think about testing when somebody comes to us and says, ‘Doc, I have a problem,’” she said, describing a historically reactive approach to medical testing. In contrast, genomic tools now allow clinicians to look earlier and more comprehensively at disease mechanisms.
Despite this shift, Lee stressed that current practice remains largely symptom-driven. In pediatrics, genomic sequencing is most often considered when a child presents with concerning features that are not explained by standard evaluations. “If it’s something that raises clinical suspicion, and none of the usual tests—the blood work, the chemistries, the imaging—reveal an answer,” she said, sequencing may offer “another lens through which we can now diagnose disease.”
Looking ahead, Lee acknowledged growing discussion around proactive sequencing earlier in life, including at birth, but emphasized that such approaches raise complex questions about choice, ethics, and readiness. “It’s not an easy-to-answer question when it should be done,” she said. While genomic sequencing may eventually become more broadly available across the lifespan, Lee underscored that today it remains a targeted diagnostic tool—used when clinical signs warrant deeper investigation.
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