Inherited retinal diseases are difficult to understand merely because they’re so rare and diverse. More than 250 genes, when mutated, can cause them, yet collectively, they affect only 200,000 people in the United States.
Their widely varying impact on vision adds to the challenge. For example, the youngest sibling in a family may be nearly blind from retinitis pigmentosa (RP), while his or her older brother or sister with the same RP gene mutation can have near normal vision.
But as FFB-funded retinal geneticist Stephen Daiger, Ph.D., discussed at the RD2016 meeting in Kyoto, Japan, the complex and elusive nature of these conditions can also extend to the way they are passed down in families, making diagnosis and prognosis quite challenging. Dr. Daiger was one of nearly 300 retinal researchers who gathered September 19-24, 2016, for the world’s largest conference focused exclusively on retinal degenerative diseases. The conference was supported in-part by FFB.
Dr. Daiger opened his discussion of unusual patterns of retinal disease inheritance by aptly quoting William Bateson, the first scientist to use the term “genetics” to describe the hereditary nature of many diseases. Even though the field was in its infancy, Bateson knew that many mysteries and roadblocks lie ahead when he said, “Embrace your exceptions.”
“It’s not only important for we geneticists to appreciate these nuances and exceptions in inheritance, it is critical that families understand the challenges as they move forward to help their loved ones,” says Dr. Daiger. “Fortunately for both scientists and families, the Foundation Fighting Blindness is unwavering in its commitment to funding research to get us the seemingly elusive answers.”
The good news: Despite the formidable diagnostic challenges, Dr. Daiger can genetically diagnose nearly 80 percent of the families and individuals with the retinal diseases, most of which are autosomal dominant,that he screens. He expects to increase that percentage to 95 by the year 2020. Innovations in genetic screening technologies and methodologies are enabling geneticists like Dr. Daiger to solve the difficult cases.
Before I review Dr. Daiger’s insights into inheritance exceptions, it may be helpful to review the three ways retinal diseases are more commonly passed down:
1) Autosomal dominant conditions: One parent is affected by the disease and has a 50 percent chance of passing the mutated copy of the gene, and the condition, to a child.
2) Autosomal recessive conditions: Neither parent is affected. Rather they are disease carriers and likely have no idea that they are. They each have a mutated copy of the gene and a normal copy. If they both happen to pass the mutated gene to their child ¾ and there is a 25 percent chance they will ¾ the child will get the disease.
3) X-Linked conditions: This pattern is more complex. Generally speaking, males are affected and women are carriers, and women have a 50 percent chance of passing the disease to their sons.
OK, let’s move on to Dr. Daiger’s talk and some of the exceptional families and inheritance phenomena he discussed. (Of course, their names were not revealed to protect their identity.)
X-Linked RP (XLRP) acting like autosomal dominant RP
A family was diagnosed with XLRP by Dr. Daiger’s lab after mutations were discovered in the gene RPGR, a common cause of the X-Linked retinal condition. Following conventional thought, only males in this family should be affected. But, alas, in this clan, many females are also affected. This “exception” is actually not all that uncommon. In recent years, researchers have found that XLRP affects a surprising number of females, who are often expected to be only carriers.
A gene normally associated with recessive disease also causes dominant
For decades, researchers have known that mutations in RPE65 can cause autosomal recessive RP and Leber congenital amaurosis. But Dr. Daiger and his team, in collaboration with Irish researchers, found that certain mutations in RPE65 caused autosomal dominant disease in two Irish families. Hence, the way a gene is mutated often has a profound way in which it causes disease and is passed down through generations.
Two different mutated RP genes in the same family
It may be difficult to imagine that one family could be affected by two different forms of an inherited retinal disease such as RP, but Dr. Daiger discovered two families in which this has occurred. In one family, some members had mutations in RP1, while others had defects in RHO. In a different family, mutations in RP1 and USH2A were affecting different members.
These three examples are by no means the only possible exceptions for retinal-disease inheritance. For instance, some people have what are called de novo mutations. That is, the mutation can’t be found in any other family member; there are no other identified affected or carrier members. Dr. Daiger also presented cases in which dominant diseases inexplicably skipped generations.
His take-home message for retinal geneticists is that they shouldn’t assume that normal inheritance patterns are necessarily at play, especially in difficult-to-diagnose cases. The exceptions underscore the need to genetically screen as many family members as possible (or practical), especially those interested in participating in clinical trials.
“If there’s anything I’ve learned over the decades of studying retinal genetics it’s to expect the unexpected,” says Dr. Daiger. “Sure there are cases of families in which things fall nicely into place. But even in those cases, there may be surprises lurking. We always need to be thorough in our analyses and keep an open mind.”