Diagnostic dilemma: A doctor discovers the genetic mutation behind a family member’s mysterious tooth loss condition

Patient: Dr. John Graham, professor of medical genetics and pediatrics at Cedars-Sinai College in Los Angeles.

Symptoms: Most newborns don’t have teeth, but Graham already had some teeth when he was born. These teeth fall out soon after birth, but adult teeth do not replace them. This is a condition known as tooth agenesis. However, over time, the rest of Graham’s mouth became filled with teeth.

What happened next: Throughout his adolescence and adulthood, Graham battled self-confidence issues and underwent multiple expensive dental implants. And he wasn’t alone. His mother and her siblings, as well as Graham’s children and grandchildren, also suffer from the condition, strongly suggesting that the disorder is hereditary.

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After graduating medical school, Graham began exploring the genetic causes of the disease.

Using genome-sequencing tools that became available in 2010, Graham struggled to pinpoint mutations hidden among the roughly 20,000 protein-coding genes in the human genome. Initial sequencing tools more than a decade ago revealed that a long DNA sequence on chromosome 1 may be involved, but this included more than 311 mutations and did little to narrow down the investigation.

Some of these mutations may even be sequencing errors. With the technology available, “the quality of the data was too noisy,” said Dr. Pedro Sanchez, director of pediatric medical genetics at Cedars-Sinai Guerin Children’s Hospital.

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

“He was my mentor during medical school,” Sanchez told LiveScience. “He inspired me to go into medicine and genetics.” Graham had spent his career helping other family members diagnose illnesses, but had not yet identified 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 identify mutations specific to people who lost their teeth. One mutation fit these criteria, and it was within the same range of chromosome 1 that Graham had previously investigated.

Diagnosis: This mutation changes one letter of the gene that codes for a protein called keratinocyte differentiation factor 1 (KDF-1). This protein regulates skin and tooth development.

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To verify that this mutation was correct, the team sequenced the genes of 21 family members. They found that this mutation appeared in 11 affected people and was absent in 10 unaffected people. This raised the possibility that genetic variation was the cause.

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

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

Sanchez and his team used computer modeling to simulate what shape the KDF-1 protein would take with and without this mutation. This revealed that the mutation altered a key component within the protein, making it unstable and misshapen. These obvious changes can cause symptoms by causing loss or alteration of the protein’s function in tooth development. They reported their findings in the International Journal of Dentistry.

Treatment: Although tooth agenesis remains an incurable disease, this discovery brought closure for Graham and his family. Ultimately, researchers believe this finding could lead to earlier diagnosis.

Sanchez also said the findings could help advocate for dental insurance companies to cover the cost of implants for affected patients, rather than treating them as unnecessary cosmetic procedures. “Tooth loss is not a cheap problem,” he said, adding that it’s important to cover dental surgery because missing teeth can make teens more susceptible to mental health problems. Underdeveloped teeth may make chewing and speaking difficult.

What is unique about this case is that while tooth agenesis, which involves a single tooth, occurs in up to 10% of Americans, the severe form that affects multiple teeth, such as the one seen in Graham’s family, occurs in less than 0.5%.

This rarity likely stems from the location of the mutation, an important part of the KDF-1 gene that has remained virtually untouched through evolution. In addition to studying human genes, the research team examined 421 animal species and found that only 10 species had evolved different genetic variants in this region.

Doctors not only solved Graham’s medical mystery; They mapped key sites on proteins important for human development.

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