Cedars-Sinai Investigators ID Gene Mutation in Dental Condition

John M. Graham, MD, ScD, doesn't remember smiling much as a child. That's because he and several of his relatives had a curious family trait: They were born with teeth, known as natal teeth, that soon fell out. For some of them, including Graham, some of their adult permanent teeth never came in.

"The natal teeth were little paper-thin teeth that fell out right away, as they didn't have well-developed roots. And, where I had natal teeth, I had no secondary teeth later in life," said Graham, a retired professor of Medical Genetics and Pediatrics and former director of the Division of Clinical Genetics and Dysmorphology at Cedars-Sinai. "The condition is called tooth agenesis."

Tooth agenesis can pose challenges such as difficulty breastfeeding, confidence issues due to missing teeth and costly out-of-pocket expenses for dental work.

Graham experienced those challenges firsthand. Correcting his missing teeth required extensive dental implants, procedures that continued well into adulthood. And as a teen active in sports, he frequently required repairs to fix chipped teeth.

The puzzling condition affected five generations of Graham's family, beginning with his maternal grandfather. Graham's mother wore false teeth for much of her life, and several of her siblings showed signs of the condition. Two of his three sons were born with natal teeth, and a granddaughter is also affected.

Graham had a strong hunch that it was an inherited genetic condition. That curiosity ultimately shaped his career. Graham pursued genetics in medical school, driven in part by a desire to understand the condition affecting his family. Years later, he began a formal search for the responsible mutation.

After more than 12 years of research, the mystery has finally been solved.

In a study published in the International Dental Journal, a team of investigators led by Graham and his longtime Cedars-Sinai colleague Pedro Sanchez, MD, identified a mutation in the KDF1 gene as the likely root cause of natal teeth. While natal teeth are relatively common and occurin approximately 1 in every 1,000 newborns, KDF-1-related multiple natal teeth with tooth agenesis is quite rare.

Finding the Gene Mutation

Finding the mutation was not a simple task. For Graham's first attempt in 2013, he ran tests on DNA samples he collected from affected and unaffected family members. But the genetic testing tools available at the time were not advanced enough to comb through the 20,000 genes in the human genome.

"In order to make a gene discovery, you have to know it's there, and you have to know what it does," Graham said. "The same gene can give rise to different genetic diagnoses. And how it does that, it's not always clear."

Years later, as Graham prepared for retirement, Sanchez, Graham's mentee and director of Pediatric Medical Geneticsat Cedars-Sinai Guerin Children's, encouraged him to revisit the research.

Sanchez credits Graham with inspiring his own path into genetics. Over the years, the two developed a close professional and personal bond, even co-authoring medical textbooks.

"I know him, I know his family, and I'm the same age as his kids," Sanchez said. "Knowing this condition had affected them for generations without closure, I felt there was a missing piece. The tools had evolved, and I believed we could work together and find an answer."

A Detailed Look Into DNA

When Sanchez revisited Graham's family data with fresh eyes and newer genetic tools, he took a more targeted approach and focused on collecting DNA samples from four family members: Graham and one affected son, as well as Graham's wife and one unaffected son, who served as controls.

This time, Sanchez deployed whole genome sequencing, a comprehensive test that analyzes a person's entire DNA sequence.

"I treated them just like a family we see in our clinic," Sanchez said. "We ended up doing a focused exam, and we sequenced all four of them."

The strategy worked.

The team pinpointed a mutation in the KDF1 gene, which is known to play a role in epidermal development, including structures like skin and teeth.

The finding doesn't offer a cure for tooth agenesis, but it opens doors to earlier diagnosis, improved counseling for families and a pathway for research into potential treatments. It may also strengthen advocacy efforts for dental insurance coverage.

For Graham, however, the impact is more than scientific. After decades of questions, the answer is finally in hand, bringing a sense of closure to a family that dealt with this trait for generations. Sanchez said he's honored to be part of the solution.

"Dr. Graham, as a mentor, taught me to be a physician," Sanchez said. "It's really nice that he was able to share the findings with his family and finally give the gene variant that has affected them for generations a name."

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