Rare Diseases, Genomics and Public Health: An Expanding Intersection

February 17, 2016 by Muin J. Khoury, Director, Office of Public Health Genomics; Rodolfo Valdez, epidemiologist, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention

Rare Diseases with DNA and an intersection

Rare Diseases with DNA and an intersection

Rare Disease Day is celebrated on the last day of February each year. On that day, millions of patients and their families around the world share their stories in order to raise awareness about rare diseases and their impact.

There are thousands of diseases that are individually rare but collectively common. In the United States, a rare disease is defined as a condition that affects fewer than 200,000 people, and rare diseases as a whole affect about 25 million people in the United States, and about 400 million worldwide. They can have severe health impact on affected patients and their families, including physical and intellectual disabilities and premature death. Examples of rare diseases include Huntington disease, fragile X syndrome, Guillain-Barré syndrome, Crohn disease, and Duchenne muscular dystrophy. In addition, the economic impact of rare diseases is substantial not only for affected patients and their families, but for society as a whole.

What does genomics have to do with rare diseases? Most rare diseases have a genetic and/or congenital cause. To date, more than 7,000 rare diseaseshave been described, although the precise genetic causes for many of them remain unknown. For about 4,300 Mendelian conditions, researchers have found underlying genetic causes. Because of the rarity of these conditions, many affected patients often go through the “diagnostic odyssey” i.e. bouncing between providers and specialists, often for years without an appropriate diagnosis or treatment.

Consider the story of a 44-year old woman who was born with congenital myasthenia syndrome. Throughout her life, she has received a number of medical opinions but it wasn’t until she was in her forties, that she received a definitive diagnosis using exome sequencing that confirmed that a particular gene mutation was responsible for her condition. A more recent example is that of a 4-year old girl whose congenital disorder had baffled doctors since she was born. She is one of the first to have a genetic abnormality identified through the 100,000 Genomes Project in the United Kingdom.

Genome sequencing has been increasingly applied in the work-up of patients with rare and undiagnosed diseases, both in the United States and elsewhere.In fact, we have seen a rapid emergence of sequencing in clinical research in the past few years. This technology has provided success in identifying new causal mutations for rare suspected genetic diseases of previously unknown cause, with diagnostic rates of 25%-50% in recent studies. In addition, over the past 4 years, the NIH funded Centers for Mendelian Genomics have conducted sequencing and analysis of protein-coding portions of more than 20,000 human genomes and have identified over 740 genes that likely cause genetic diseases.

Molecular genomic diagnosis of rare diseases can lead to changes in medical care including use of existing medications or development of new ones to help people with specific mutations, as well as discontinuing ineffective therapies. For example, one child diagnosed by genome sequencing with early infantile epileptic encephalopathy type 11, a severe, genetic form of epilepsy that is amenable to treatment with a ketogenic diet, was switched to a high-fat diet, which reduced the frequency of seizures. Molecular insights have not led to effective therapies for most rare diseases so far, but they do promise deeper understanding into the biology of these conditions that could lead to better management and improved outcomes in the future. For an increasing number of rare diseases, treatments are becoming readily available, which can ameliorate or reduce the burden of illness and delay death. Examples include cystic fibrosis, hemophilia, sickle cell disease and phenylketonuria. Obviously, these are the early days of the application of whole genome sequencing in rare disease research and management and many scientific, ethical and societal challenges remain.

What does public health have to do with rare diseases? At its core, public health is an organized effort by society to keep its members healthy and to prevent disease and disabilities. Public health is no stranger to the world of rare and genetic diseases. For more than half a century, newborn screening for selected metabolic and other rare genetic conditions has been a major public health program in the United States and many countries around the world. These programs have arisen because of the availability of life or disability saving interventions coupled with the ability to perform timely diagnoses and treatments early in life. The number of screened conditions has increased steadily over time with more than 30 disorders now recommended by theAdvisory Committee on Heritable Disorders in Newborns and Children.

Aside from newborn screening, the applications of public health approaches to rare genetic diseases remain limited. There are many reasons for this including the fact that ”patients are few and scattered” and “approaches based on identifying and removing risk factors are generally not well-suited for diseases whose primary risk factors are…irremovable.”

Recent activities have included expansion of public health surveillance, research and education for some rare diseases such as muscular dystrophy andamyotrophic lateral sclerosis. Nevertheless, there is an emerging opportunity for a comprehensive public health approach to rare diseases. A confluence of factors makes the case even more compelling, including a mobilized and empowered patient community, better genomic and other technologies for diagnosis and treatment, and increasing interest[PDF 1.96 MB] in developing precision interventions.

What would a public health comprehensive approach look like?

The 10 essential public health services apply to all diseases including rare diseases. In particular, there are many elements and benefits of these applications as described in a recent issue of Preventing Chronic Disease. Just to name a few, a public health comprehensive approach includes: 1) evaluating disease burden and health impact; 2) conducting surveillance by developing and implementing population-based registries; 3) enhancing our knowledge of natural history and interventions, developing clinical guidelines; 4) conducting etiologic research; 5) evaluating health care practices and outcomes; 6) identifying and disseminating evidence-based findings on best practices and standards of care; 7) ensuring equity in implementation of treatments and interventions across the population.

Finally, as the Precision Medicine Initiative gets implemented, there will be many more opportunities at the intersection of rare diseases, genomics and public health. As more research into the molecular foundation of rare diseases leads to new discoveries and interventions, a major public health effort will be needed for delivering the appropriate interventions to all patients with rare diseases in the United States and around the world.

So, in recognizing February 29, 2016 as Rare Disease Day with thousands of events happening around the world, we want to help build awareness about people living with a rare disease and their families by highlighting the opportunity to apply public health approaches to improve their health and reduce their burden of disease and disability.