WHAT IS A MYSTERY GENETIC DISEASE?
Diseases of genetic origin might cause symptoms at birth or manifest later in life. By age 25, more than 5% of the population has a disorder that has an important genetic component. Thus approximately 16 million people in the United States are affected. In many cases, the underlying genetic variant is not known.
Genetic disorders that cause symptoms early in life often, but not always, are caused by a variant in a single gene. We call this type of disorder “monogenic.” Genetic disorders attributable to variants in a single gene follow predictable inheritance patterns as originally described over one hundred years ago by the father of genetics, Gregor Mendel. These disorders are often described as “Mendelian” and can be either recessive (i.e., the copies of the gene from both mother and father each carry a mutation for the disorder to be manifested) or dominant (i.e., only one defective copy of the gene is needed for the disorder to develop) (Figure 1).
Sickle cell disease is an example of a Mendelian, recessive disease. Individuals who inherit the sickle variant of the hemoglobin β -globin gene HBB from both their mother and father have the characteristic sickle-shaped red blood cells (our oxygen-storing cells). This shape causes these cells to become abnormally fragile, leading to anemia (low red blood cell count and oxygen deprivation) and a host of other problems. Individuals who inherit a normal β -globin gene from one parent and a sickle variant β -globin gene from the other parent do not have the disease, because the normal copy of the gene is sufficient to supply functional hemoglobin to red blood cells. An example of a dominant Mendelian disorder is osteogenesis imperfecta (brittle bone disease), which is most commonly due to a mutation in a gene for type 1 collagen, an important constituent of bone. Because the mutant type 1 collagen interferes with the function of normal type 1 collagen, an individual inheriting a defective gene from only one parent still exhibits the disease. At one point in time, these diseases were considered “mystery diseases,” with the genetic cause unknown; in many cases, decades of research went into discovering the causative genes.
Figure 1. Recessive and dominant mutations. Recessive mutations are those that need to be present in both gene copies for disease to arise. “Homozygous mutations” refers to when each gene copy carries the same mutation; “compound heterozygous mutations” refers to when each gene copy carries a mutation, but the mutations are different. Dominant mutations require only one copy to be mutated to cause disease.
Mendelian disorders may run in families (be familial), or they may arise spontaneously in the germ cells (egg and sperm cells) of the mother or father (or after the fusion of the sperm and egg) and be “de novo” to the child (i.e., not present in the mother or father outside of the germ cells). Thus, when a child with a disorder of suspected genetic origin is born to healthy parents, a spontaneous dominant variant or an inherited recessive variant are the most likely causes. Adding more complexity, disease-causing variants may vary in their “penetrance,” that is, in how frequently individuals who carry those variants manifest symptoms of the genetic disease. Highly penetrant variants cause disease in a large proportion (or even all) individuals who carry those variants.
Before the current era of rapid and relatively inexpensive genome or exome sequencing, patients with mystery genetic diseases typically underwent extensive testing and inappropriate treatments before the basis of their disease was understood. It is estimated that it costs $5 million per person to manage these diseases over a person’s lifetime. Thus, prompt detection and proper diagnosis of these diseases using new DNA sequencing technologies not only ensures that the afflicted individual receives the appropriate medical care, but also helps realize an enormous savings in healthcare costs. Furthermore, patients and their families are spared unnecessary, stressful, and time-consuming testing. Although not all mystery genetic diseases are solvable using current technologies (see more below), the advent of genomics has dramatically improved success rates.