Finding Answers for Rare Diseases

Genome sequencing can identify genetic variants that may cause disease, but the answers aren’t always clear. Variants of uncertain significance (VUS) can cloud the picture, leaving patients and families in a diagnostic no-man’s land.

Now, in a study published in the American Journal of Medical Genetics, researchers at the University of Miami Miller School of Medicine have shown that carefully reevaluating VUS can generate concrete diagnoses. These approaches could help physicians and researchers solve numerous medical mysteries, potentially matching patients with effective treatments and clinical trials.

“A large proportion of potential genetic cases remain unsolved, despite genome or exome sequencing, and the work to reach a diagnosis should not stop with a negative or inconclusive clinical report,” said Pankaj Agrawal, M.D., chief of the Division of Neonatology at the University of Miami Miller School of Medicine Department of Pediatrics and Jackson Health System. “It’s critical to keep working on these cases through re-analysis of data to identify novel genetic variants, research experiments to evaluate them and working collaboratively to find answers.”

Identifying Genetic Causes of Disease

Dr. Agrawal, who was senior author of the study, and colleagues have spent years developing methods to identify genetic variants that drive disease. Their 2019 study highlighted how data reanalysis could identify disease-causing genes. However, a large group of variants remained uncharacterized.

The researchers spent the next four years pursuing answers. They tested variants in cellular and animal models, referred to public databases and contacted collaborators at other institutions. Over time, their persistence paid off.

“We had identified 33 such candidate gene-variant cases in 2019 and, over four years, we solved 16 of them,” said Agrawal. “We were able to establish causal links between the variants and the patients’ diseases, providing definitive diagnoses.”

In one case, a Danish family had two children suffering from phenylketonuria (PKU), an inherited disorder that can generate neurological problems, rashes and other issues. One child’s disease was controlled with diet and other interventions. The second child had unusual complications, including dire infections, and died before his second birthday.

The culprit was a mutated EIF2AK2 gene, which normally supports innate immunity. The lab conducted rigorous cell tests to better understand the mutation. Through a worldwide database, GeneMatcher, the Agrawal lab found that researchers at Baylor University had been working with variants in the same gene and had seen similar presentations in other patients.

“EIF2AK2 mutation was a great candidate, but that meant nothing until we proved it was the actual, disease-causing variant using cellular models that explained the child’s worsening condition,” said Dr. Agrawal. “This was a new mutation and identifying it gave the family the answers they needed.”

Spurring Knowledge and Treatment for Rare Diseases

This work can have a ripple effect for both rare disease families and drug discovery. Because these conditions are so rare, most physicians have never seen a single case in their careers. Families rely on researchers for new information.

Recently, the Agrawal lab found that EIF4A2 is a novel gene that, when mutated, can cause difficult-to-treat seizures and other neurological issues. For one mother in North Carolina, this critical news revealed the gene behind her child’s illness.

“We stay in touch by email, and she found another family with the same genetic condition and learned by trial and error that a particular, two-drug combination controlled the seizures better,” said Dr. Agrawal. “I was excited about this finding, and while this is early and anecdotal evidence, we can share that information with other affected patient families, and they may potentially benefit from this approach.”

Tags: Dr. Pankaj Agrawal, genomics, neonatology, rare diseases