A team of international scientists has uncovered the genetic underpinnings of a rare, inherited autoimmune disorder, according to a study recently published in Science Translational Medicine.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a life-threatening autoimmune disease that affects an estimated 1 in 100,000–500,000 people worldwide, according to the National Institutes of Health.

People with APECED may experience more than 30 different manifestations of the disease, including chronic fungal infections of the skin and mouth, endocrine dysfunction and multi-organ inflammation.

While the disease is known to have genetic causes, not all patients with the condition have the hallmark variant in the AIRE gene, said Jennifer Miller, MD, '04 GME, associate professor of Pediatrics in the Division of Endocrinology, who was a co-author of the study.

"We saw a patient in clinic with APECED, and we knew she had this clinical picture, but we didn't know why, because all of her genetic testing had been normal," Miller said.

In the study, scientists from several countries worldwide performed genetic sequencing on 17 patients who had APECED but didn't have the expected genetic variants. They discovered that the genetic variance lay in the non-coding region of the AIRE gene, according to the study.

"It's not a variant in the expressed gene, but in a non-coding region within the gene, which causes frame-shifting and failure of AIRE gene function, leading to the same APECED clinical picture as we see with previously known AIRE variants," Miller said.

By analyzing kidney and thymus cells cultured with the AIRE mutation, investigators found that the variant altered the AIRE protein, halting normal function.

According to the study, 15 of the 17 participants were of Puerto Rican ancestry, a finding which may aid in future patient screening for APECED.

"We have so many genetic tests at our fingertips now, and it's amazing to be able to get diagnoses based on genetics. But this tells me that if you have someone who fits a clinical scenario, even if their genetics don't match up with what you expected, it doesn't mean there's not an underlying genetic variant, just that we may not have tested for it," Miller said.

Miller hopes to build upon this work to improve treatment options for her patient, with the hopes of getting insurance to cover more effective and convenient medications for hypoparathyroidism associated with APECED, she said.

"From a clinical perspective, the next step for me is continuing to work with some of the authors from this paper to try to get medications approved for hypoparathyroidism in children as an alternative to the conventional therapy, which is very tedious and involves taking multiple medications throughout the day," Miller said.

Miller said she's grateful for the international collaboration that yielded new answers for her patient.

"I had one patient and clinicians elsewhere else had one patient, and we all found this research site and were able to create a robust, convincing story, which essentially proves that this genetic change is responsible for these patients' clinical picture," Miller said.