Watching a loved one suffer from an unexplained health problem is excruciating, especially when, after countless doctor visits and dozens of tests, families are still left without answers.
Many neurodevelopmental disorders have genetic causes. Thanks to advanced sequencing technologies and a growing understanding of the human genome, the odds of receiving a long-awaited diagnosis are improving.
In this episode of Tiny Expeditions, we explore how researchers at HudsonAlpha are working to change that story—one gene at a time. We dive into a remarkable case involving more than 20 children across North America, Europe, and Eurasia, all sharing similar neurodevelopmental symptoms and genetic variants in a little-known gene.
Using an innovative matchmaking tool for genetic data and a range of lab techniques, scientists around the world joined forces to uncover the gene’s role in this rare disease and bring hope to affected families.
Join us for Tiny Expeditions Season 6, Episode 2, “DNA Clues: Diagnosing the Undiagnosed,” as we explore the science behind genetic discovery. We will go behind the scenes in the lab to learn how researchers study genes like ZMYM3 and how their work helps families find long-sought answers.
Behind the Scenes
Meet Our Guests
From one patient to a global network
Throughout this episode, we talked with our guests about a global collaboration they both participated in to help find answers for a cohort of unrelated children with similar neurodevelopmental delays and intellectual disabilities. It is a fascinating story of discovery, collaboration, and hope.
On an ordinary day in the Cooper lab at HudsonAlpha, Dr. Susan Hiatt was analyzing the genome of a child with unexplained developmental delays. She flagged a few interesting variants that she investigated further, eventually landing on a variant in a gene called ZMYM3.
Following their standard lab practice, Dr. Hiatt submitted the gene variant to GeneMatcher, a powerful online platform that serves as a kind of matchmaking service for genes. It connects researchers and clinicians working with patients who have variants in the same gene, enabling collaboration across borders.
This one submission for ZMYM3 sparked a massive response: over the next four years, at least 30 different researchers around the world contacted Dr. Hiatt. They also had patients with unexplained neurodevelopmental delays and ZMYM3 mutations.
Building the case, one patient at a time
Through these connections, a collaborative team formed. Together, they assembled a cohort of 27 individuals with 22 different variants in ZMYM3. Most were males who had inherited the variant from their mothers, but six children had de novo variants (spontaneous mutations not inherited), suggesting that the gene may be directly involved in disease development.
To validate their findings, the team needed to answer two questions:
- What is ZMYM3 normally responsible for?
- How do these variants change what the gene and its protein do?
That’s where Dr. Chris Partridge from the Myers lab stepped in.
What Does ZMYM3 Do?
ZMYM3 encodes a type of protein called a transcription factor. Think of transcription factors as cellular switches: they bind to specific parts of DNA to turn genes on or off, regulating when and how much specific proteins are made.
Many transcription factors act like managers, ensuring that the right genes are activated at the right time during brain development—a process that, when disrupted, can lead to developmental delays or cognitive impairment.
The importance of foundational research
To understand exactly how the ZMYM3 variants affect the protein’s function, Dr. Partridge used CRISPR gene editing to introduce the mutated gene into lab cells. His goal was to see where and how the altered ZMYM3 protein behaves differently from the healthy version.
Using microscopy, the team looked at where ZMYM3 proteins localized in the cells. The healthy copy of the protein traveled into the nucleus, where it could bind DNA and do its job as a transcription factor. However, in cells with the mutated version, ZMYM3 wasn’t making it into the nucleus at all. Without access to DNA, the protein simply couldn’t regulate genes, potentially disrupting key developmental pathways.
You can actually see this difference for yourself in the lab images below.
Why It Matters
This collaboration was powered by data sharing and rooted in foundational research. It did more than just link a gene to a disease; it gave families answers after years of uncertainty and expanded the scientific understanding of how ZMYM3 functions in neurodevelopment.
Since 2016, the Cooper lab has submitted 413 genes to GeneMatcher, resulting in more than 80 collaborations and 32 peer-reviewed publications. The ZMYM3 study is a prime example of how genetic tools, international teamwork, and basic research combine to change lives.
If you’re interested in learning more about the study, you can access the publication in the American Journal of Human Genetics.
