The process of gene discovery can be a difficult concept for many people to comprehend. Just trying to understand a genetic condition after receiving a diagnosis can be a challenge. However, understanding the science behind that condition can help patients and their families grasp what goes on behind the scenes and why research takes so many years to complete.
People unfamiliar with genetic research many imagine it involves scientists running around in lab coats, peering into microscopes and talking in complicated scientific jargon. However, the process of genetic research is actually more like solving a mystery through detective work. Researchers put together the clues, try to find the culprit (the disease-causing gene) and attempt to piece together what happened (how a change in that gene leads to the disease’s symptoms).
Here we will explore how we learned about BPAN—what separated it out from other types of NBIA, how we found the gene, and what we know about the symptoms. By the end of the story, genetic research will seem less like a foreign language and more like an episode of your favorite detective show.
What is the mystery that needs to be solved?
Research starts with an unanswered question. In the case of genetic disease research, that means starting with a patient who has symptoms that don’t fit any known disease. If doctors can’t figure out what disease an individual has, it becomes much harder to treat them and to prevent or slow down additional symptoms that might develop later.
Rare conditions like the NBIA disorders were extremely difficult to classify in the past because the individuals who had them were spread out across the world. Now, due to the widespread use of scientific journals and online databases, it’s easier for doctors to report and share patients who have unusual symptoms they’ve never seen before. Eventually, doctors and researchers who work on rare conditions may begin to notice patterns among certain patients with unknown diseases. Once they see a pattern forming, the detective work can begin.
In the case of BPAN, our starting point was a small group of patients with a few key findings that made them special. Unlike any other NBIA patients, they had developmental delay from an early age but were stable medically until young adulthood. Then, they developed parkinsonism and other movement problems that progressed over time. This was when they usually had a brain MRI, and iron was noticed. These patients were so similar to one another that we thought they must all share the same changed gene. And, although it took us a while, we eventually noticed that most of them were female, and none of them had affected brothers or sisters. So, the mystery that needed to be solved was figuring out what altered gene was causing their symptoms and what the range of symptoms looked like.
Gathering the evidence
Like all good detectives, genetic researchers begin by gathering the available evidence or clues. In the case of BPAN, this meant gathering data from our small group of similar patients—medical reports, brain images, and descriptions from their families. We had met many of them over the years, so we even had photos and videos from some. By including patients with the most similar symptoms in the study group, investigators can dramatically increase the odds of finding a common cause for those symptoms.
Finding the common link
We first recognized the similarities among this group more than a decade ago, and for many years we used different technologies to hunt for a common gene. When NBIA conditions were first being investigated, the process of gene discovery was like finding a needle in a haystack. Human DNA is made of thousands of genes, and it took years just to figure out which section of the DNA might contain the gene we were looking for. However, due to advances in technology, that process has now become simpler and much faster.
The gene responsible for BPAN was eventually discovered through a new process called whole exome sequencing. This process is like running a spell-check program on your DNA. Sequencing breaks down the DNA into individual genetic components, or “words and letters,” so a sophisticated computer program can see if there are any changes or “spelling mistakes.” When our group had their DNA analyzed, it was discovered that all but one had changes in the same gene, WDR45. This gene sits on the X chromosome, one of the 2 sex chromosomes.
To make sure WDR45 was really the responsible gene, researchers used a confirmation method. They selected a total of 60 individuals from the OHSU NBIA registry and other international NBIA registries. None of the individuals selected had a known NBIA gene. The WDR45 gene was sequenced to see if other patients a change in that gene. Sure enough, some more cases were found. In the end, all the patients with a WDR45 gene change were found to have similar symptoms and MRI findings. This was even better evidence that the mystery had been solved.
Finding the WDR45 gene solved some additional mysteries about BPAN. First, why does it usually affect girls? The WDR45 gene sits on the X chromosome, one of the 2 chromosomes that decide sex. Females have two X chromosomes, while males have one X and one Y. X-linked conditions often affect females more than males, because females have a “back-up” X that can help them tolerate the change. It is likely that most males with BPAN miscarry early in pregnancy because they don’t have this back-up system. Second, why does BPAN happen only once in a family? After the gene was found and the parents and siblings were checked, we discovered that the gene change is new in the affected individual. This type of new change is called “de novo.” De novo gene changes are not inherited from a parent. Instead, they occur spontaneously. This can happen in the sperm or egg that leads to a pregnancy, or it can happen during early embryo development.
Unanswered questions that remain
In detective cases, the motive is often the most difficult question to answer and often contains many holes. This is also true in the case of BPAN. Even though we’ve discovered what altered gene leads to BPAN, we still don’t fully understand how a change in that gene causes all the symptoms we see.
WDR45’s main job is to help the body’s cells break down some of their components and recycle the parts to form new components. This process is known to be damaged in many other neurodegenerative disorders, but we still don’t understand how it specifically leads to BPAN symptoms.
How can genetic research be applied to the real world?
Once a disease gene is discovered, the next step is figuring out how to use the information to help patients. The most immediate way a disease-causing gene discovery helps is by making it easier to diagnose that disease. The diagnosis process becomes faster, has less room for error, and often leads to earlier diagnosis with fewer unnecessary, invasive tests. In many cases, an earlier diagnosis leads to better outcomes because medication can be started sooner and doctors can monitor for symptoms that are known to develop later.
Gene discovery can also help the parents of the individual who was diagnosed with a genetic condition. If a couple has a child with a genetic condition, they often wonder what the chances are to have another affected child. For some genetic conditions, the chance can be up to 50%. In those cases, parents may chose to not have any additional children or may undergo genetic testing during pregnancy. In the case of BPAN, it was discovered that the gene change is new and not inherited, which is important information for the parents and siblings to understand.
Finally, we have also learned that many individuals with BPAN share symptoms with another genetic condition called Rett syndrome. This has led to a new study to investigate whether some patients with Rett syndrome actually have WDR45 gene changes.
- Visit our Learn section for more information about BPAN
- Visit our BPAN-Rett Project page to learn about the BPAN and Rett syndrome research study
- “Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation” by S. Hayflick and colleagues
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