The patient: Dr. John Grahamprofessor of medical genetics and pediatrics at Cedars-Sinai in Los Angeles
The symptoms: Most newborn babies have no teethbut Graham already had a few when he was born. These teeth fell out very soon after birth, but adult teeth never replaced them – a condition known as tooth genesis. In time, the rest of Graham’s mouth filled with teeth.
What happened next: Throughout her adolescence and adulthood, Graham struggled with self-esteem issues and underwent several costly dental implants. And he wasn’t alone – his mother and her siblings, as well as Graham’s children and grandchildren, also had the condition, strongly suggesting that the disorder was genetic.
After graduating from medical school, Graham set out to hunt for a genetic cause of the condition.
With the genome sequencing tools available in 2010, Graham struggled to find the mutation hiding among 20,000 or so protein-coding genes in the human genome. Those early sequencing tools from over a decade ago revealed that a long stretch of DNA sequences on chromosome 1 was likely involved, but this came with over 311 mutations to pore over, hardly limiting the search.
Some of these mutations may even have been sequencing errors. With the technology available, “the quality of data was just way too noisy,” he said Dr. Pedro Sanchezdirector of pediatric medical genetics at Cedars-Sinai Guerin Children’s.
Graham was preparing to retire and at the same time stop looking for the problem gene when Sanchez offered to help Graham continue the hunt.
“He was my mentor in medical school,” Sanchez told LiveScience. “He motivated me to go into medicine, into genetics.” Graham had spent his career helping to diagnose other families’ illnesses, but had yet to diagnose his own. “Right before he retired, I said, ‘I have to do this for you,'” Sanchez said.
To narrow down the genetic cause, Sanchez and his colleagues sequenced and compared the genomes of two affected and two unaffected family members to isolate mutations unique to individuals with missing teeth. One mutation fit these criteria, and it was located within the same stretch of chromosome 1 that Graham had explored earlier.
The diagnosis: The mutation caused a one-letter change in the gene that codes for a protein called keratinocyte differentiation factor 1 (KDF-1). The protein regulates development of skin and teeth.
To validate the mutation as the correct one, the team sequenced the gene in 21 family members. They found that the variant appeared in 11 affected individuals and was absent in 10 unaffected individuals. That cemented the genetic variant as the likely cause.
Picture 1 of 2
Using computer modeling, Sanchez and his team simulated what form the KDF-1 protein would have with and without this mutation present. This revealed that the mutation changed a critical building block in the protein, thereby destabilizing and bending the protein out of shape. Such an obvious change can cause the protein to lose or change its function in tooth development, leading to the condition. They reported this discovery in International Dental Journal.
The treatment: Tooth decay remains incurable, but the discovery offered Graham and his family closure. Down the line, this discovery could lead to earlier diagnosis, the researchers believe.
Sanchez also said the discovery could help advocate for dental insurance providers to cover the cost of implants for affected patients, rather than treat implants as non-essential cosmetic procedures. “Tooth generation is not a cheap problem to have,” he noted, adding that it is important to cover dental surgery because missing teeth can predispose teenagers to mental health problems. Tooth agenesis can also do chew and talk more difficult.
What makes the case unique: Dentogenesis involving a tooth occurs in up to 10% of Americansbut the severe form affecting multiple teeth—as seen in Graham’s family—occurs in less than 0.5% of people.
This rarity probably stems from the location of the mutation: a critical site in the KDF-1 gene that evolution has left virtually untouched. In addition to studying the gene in humans, the team looked at 421 animal species and discovered that no more than 10 species had evolved a different gene variant at this location.
The doctors didn’t just solve Graham’s medical mystery; they mapped a crucial site on a protein important for human development.
For more exciting medical cases, check out our Diagnostic Dilemma Archives.
Graham, JM, Sanchez-Lara, PA, Ohazama, A., Kawasaki, K., Arold, ST, & Kantaputra, PN (2025). A new KDF1 variant is associated with multiple birth teeth, tooth agenesis and root defects. International Dental Journal, 75(4), 100860. https://doi.org/10.1016/j.identj.2025.100860
