Diagnostic dilemma: A doctor discovered the gene mutation behind his family's mysterious missing-teeth condition

The patient: Dr. John Graham, a professor of medical genetics and pediatrics at Cedars-Sinai in Los Angeles

The symptoms: Most newborn babies don't have any teeth, but Graham already had a few when he was born. These teeth fell out very shortly after birth, but adult teeth never replaced them — a condition known as tooth agenesis. With time, though, the rest of Graham's mouth filled with teeth.

What happened next: Throughout adolescence and adulthood, Graham contended with confidence issues and underwent multiple costly dental implants. And he was not alone — his mother and her siblings, as well as Graham's children and grandchildren, also had this condition, which strongly suggested 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 pinpoint the mutation hiding among the 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 narrowing down the search.

Some of those mutations may have even been sequencing errors. With the technology available, "the quality of data was just way too noisy," said Dr. Pedro Sanchez, director of pediatric medical genetics at Cedars-Sinai Guerin Children's.

Graham was preparing to retire and simultaneously stop searching for the problem gene when Sanchez offered to help Graham continue his pursuit.

"He was my mentor in medical school," Sanchez told Live Science. "He motivated me to go into medicine, into genetics." Graham had spent his career helping to diagnose other families' illnesses but had yet to pin down 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 the individuals with missing teeth. One mutation fit those criteria, and it lay within the same stretch of chromosome 1 Graham had explored previously.

The diagnosis: The mutation caused a change to one letter in the gene that codes for a protein called keratinocyte differentiation factor 1 (KDF-1). The protein regulates the 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 people. That cemented the genetic variant as the likely cause.

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Dr. John Graham (top row center) with two of his sons and their families at Christmas.

Dr. John Graham (left) with Dr. Pedro Sanchez at a Los Angeles Dodgers game.

Using computer modeling, Sanchez and his team simulated what shape the KDF-1 protein would take with and without this mutation present. This revealed that the mutation changed a critical building block within the protein, thus destabilizing and bending the protein out of shape. Such an overt change could cause the protein to lose or alter its function in tooth development, bringing about the condition. They reported this discovery in the International Dental Journal.

The treatment: Tooth agenesis remains incurable, but the discovery offered Graham and his family closure. Down the line, this discovery may lead to earlier diagnosis, the researchers think.

Sanchez also said the discovery could help with advocating for dental insurance providers to cover the cost of implants for affected patients, rather than treat implants as non-essential, cosmetic procedures. "Tooth agenesis is not a cheap problem to have," he noted, adding that it's important to cover dental operations because missing teeth could predispose teenagers to mental health issues. Tooth agenesis can also make chewing and speaking more difficult.

What makes the case unique: Tooth agenesis involving one tooth occurs in up to 10% of Americans, but the severe form affecting multiple teeth — as seen in Graham's family — occurs in less than 0.5% of people.

This rarity likely stems from the mutation's location: 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 site.

The doctors didn't just solve Graham's medical mystery; they mapped a crucial site on a protein important in human development.

For more intriguing medical cases, check out our Diagnostic Dilemma archives.