Rare Disease Project Makes Progress, Empowers

Imagine facing a devastating medical problem, but when you searched for a diagnosis, even the experts had no answers because your condition was so rare.

In the U.S., a disease is considered rare if it affects fewer than 200,000 people. Many rare diseases have genetic origins, and almost 70 percent of Americans affected by a rare disease are children, according to the National Organization for Rare Disorders (NORD).

NORD recently hosted Rare Disease Day USA, when the U.S. joined more than 80 nations around the world to focus attention on rare diseases as an important global public health challenge. Rare Disease Day also presented the opportunity to recognize the important gains made through international cooperation in clinical and scientific research.

Under a collaboration announced in 2012, The Children’s Hospital of Philadelphia and BGI, the world’s largest genomics organization, initiated the 1,000 Rare Diseases Project to accelerate the discovery of genetic variants underlying rare diseases. By using next-generation sequencing (NGS) technologies, researchers from CHOP and BGI are one-third of the way toward their goal of sequencing 1,000 rare diseases.

“We have made major progress,” said Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at CHOP who directs the project. “A number of our discoveries have exciting potential because there are existing drug therapies that could be repositioned or repurposed for some of these rare diseases we have now resolved. That will be a big impact.”

One of the project’s first success stories involved a family that had been coming to CHOP for almost 20 years. The parents wanted to track down the disease that caused their son and daughter to have progressive muscular weakness and also weakening of the heart muscle (cardiomyopathy) beginning at age 8.

Through whole-genome sequencing, the research team located RBCK1, a disease-predisposing gene for a novel and extremely rare single-gene disorder that had never been identified before. Genetic mutation shortens the protein that RBCK1 encodes, and then the modified protein accumulates in muscle fibers. Researchers confirmed that truncating mutations in RBCK1 were the culprit when they found the same exact gene to be mutated in a second family that had a comparable disease profile. Genome Medicine published their findings in 2013.

“It was very rewarding,” Dr. Hakonarson said. “The families have been fundraising for us so that we can gain a better understanding of the mechanism by which the gene mutation causes this devastating disease.”

Another study published in the American Journal of Human Genetics determined that mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis (AD IM). The disorder arises in infancy and childhood and is characterized by proliferative fibrous tumors affecting the skin, muscle, bone, and internal organs. Researchers performed whole-exome sequencing in members of nine unrelated families diagnosed with AD IM to identify the genetic origin of the disorder. In addition to pinpointing PDGFRB, they highlighted NOTCH3 as another disease-causing gene for IM.

“Both of these genes have been targeted by drugs that pharmaceutical companies have developed for totally different diseases,” Dr. Hakonarson said. “We have the opportunity to make a big shortcut here to develop new therapies to treat this disease.”

Other studies published by the investigators have shown:

• mutation in ANKRD26 causes thrombocytopenia, a rare platelet disorder
• mutation in ABCC6 causes generalized arterial calcification of infancy
• a subset of mutations in DcR3 have a role in pediatric-onset inflammatory bowel disease
• HK1 is a likely disease gene candidate for a novel congenital hyperinsulinism disorder.

Overall, the researchers have collectively identified between 40 and 50 new diseases so far, and they continue to make discoveries that elucidate rare diseases and resolve weighty questions for families.

“When we find these new mutations, the clinicians who treat these families have been able to validate these mutations by rigorous clinical testing and inform families that this is the disease-causing gene, and they have been immensely appreciative,” Dr. Hakonarson said. “They can go to other geneticists and clinicians and share these results. Now that they know what causes the disease, they can have other family members tested, and prenatal testing becomes an option for future pregnancies.”