Shining light on one family’s struggle: Barbara, Deborah, Pamela, and Rylie
Before they went through testing at Mayo Clinic Laboratories, Barbara Domaille, Deborah Neville, Pamela Neville, and Rylie Ronnenberg thought there could be a genetic connection to the hip problems they shared. After the testing, they knew for sure.
As family members, Barbara Domaille, Deborah Neville, Pamela Neville, and Rylie Ronnenberg share many things in common that they treasure, and only one they wish they didn’t: a hip abnormality called femoroacetabular impingement.
After undergoing genetic testing at Mayo Clinic, the four women learned that their collective hip woes were caused by a hidden genetic connection. And although that knowledge may not change how their condition is managed, it does offer some relief from nagging concerns. It also may provide researchers with information that could help others.
“We said yes [to testing] to try and stop some other family from having to go through this, because it’s not fun,” Deborah says. “We also wanted an answer to a question that’s been in the back of our minds for a while: ‘Is this something that genetics is causing to happen?’”
Four generations of pain
Hip impingement occurs when the ball and socket of the hip joint do not fit together properly. Over time, the restricted motion caused by hip impingement can damage cartilage and cause pain and arthritis. For great-grandmother Barbara, the condition eventually led to the need for hip replacement surgery, as it did for her daughter Deborah. “I have actually had both of my hips replaced,” Deborah says.
Deborah’s daughter, Pam, followed in her mother’s and grandmother’s unfortunate footsteps after her hips “literally went out” while playing coed softball in her 30s. “That’s when I knew I needed to have hip surgery, too,” Pam says.
Rylie, the youngest of the women and Pam’s daughter, has endured just as many hip-related problems as her elder female family members. “I had my right hip done in 2018 and my left hip done in 2020,” the first-year college student says.
Before their surgeries, all four generations of women say they experienced similar symptoms. “It was very painful for all of us to walk and move, and there was a lot of clicking and popping in our hips,” Pam says. On a few occasions, Rylie’s clicking and popping was so severe that her left hip felt as though it had popped out of its socket. “Just while I was walking around at school,” she says.
Clockwise from the top left: Rylie Ronnenberg, Pamela Neville, Deborah Neville, and Barbara Domaille
Bad luck or altered genes?
During the course of treating each family member for their respective hip problems, their Mayo Clinic orthopedic surgeon, Rafael Sierra, M.D., began to wonder if their shared condition was due not to bad luck, but altered genes.
“I was in his office one day after my surgeries, and he asked if he could enroll us in a research study,” Deborah says. “By that time, Pam had started having hip problems, and he’d done multiple surgeries on my mom. I told him I’d participate because I thought it was really strange that we were all having similar problems.”
Less than a month later, Dr. Sierra had received consent from Barbara, Pam, and Rylie, as well. “When Dr. Sierra talked to me about the study, he told me he’d had a good time at one of his staff meetings because he’d put our hip X-rays up and asked people what they saw,” Pam says. “Everyone thought the X-rays were from the same person, just at different ages. When everyone learned the X-rays were from four different people in the same family, they agreed it would be interesting to see if there was a genetic link to our problems.”
To answer that question, all four women agreed to undergo whole exome sequencing at Mayo Clinic. Whole exome sequencing is a diagnostic genetic test that targets a patient’s exome, which represents approximately 1% to 2% of the genome. It uses a process of next-generation sequencing to capture the exome.
“By annotating that data and using several filtering approaches, we’re able to narrow down to a few hundred variants, in most cases, that we then systematically go through, either as molecularly interesting variants, or variants that fit a particular inheritance pattern,” says Cherisse Marcou, Ph.D., clinical co-director of Mayo Clinic’s Genetics and Genomics Laboratory. “We overlay that with gene disease association in order to try to identify causative variants or variants that have a genetic mechanism that would be suspicious for that patient’s phenotype. It’s an approach that allows us to take a global view of the coding regions of each individual’s genome to compare and determine what might be occurring privately in a family.”
Benefits for the future
Barbara, Deborah, Pam, and Rylie had their testing done at Mayo Clinic’s Genomics Core Facility in Rochester, Minnesota. When the results came back, Dr. Sierra’s coinvestigator and orthopedic surgery resident Cody Wyles, M.D., says the family’s shared hip problems began to make more sense.
“We found some candidate genes that were changed in all four generations of women.” Dr. Wyles says. “One of the genes in particular that was altered is very notably involved in the development of the hip joint.”
Specifically, Dr. Wyles says the family’s test results showed that across the entire coding region of the genome, 43 genes were different. “These networks included several genes that are highly expressed in bone tissue and known to be critical for bone morphogenesis and homeostasis,” he says.
According to Dr. Wyles, the fact that multiple genes implicated in bone formation were different in each family member is not only unique but also could lead to additional research and an improved understanding of how femoroacetabular impingement develops in the body.
“While these test results aren’t likely to provide Barbara, Deb, Pam, and Rylie with any direct benefit outside of now knowing for sure that there is a genetic connection to their hip problems that future generations can be screened for at even younger ages, their results are going to help future generations of patients,” he says. “That’s what we’re working on now — trying to find if there are target populations in particular that we should be testing at young ages. It’s definitely giving us clues into not just how femoroacetabular impingement happens, but also a way to identify patients with the condition that we never could before. I definitely think their participation in this testing is going to help future generations.”
Eric Wieben, M.D., director of Mayo Clinic’s Medical Genome Facility, agrees. “Really, what you’re thinking about with testing like this are the following generations,” he says. “And for any kids they might have, we now have a specific gene alteration to look for in those children if they want to have it looked for.”
Whole exome sequencing also can help drive and advance future research.
“A lot of times, results will help open up new lines of research into a specific gene where these alterations are found that are associated with a disease,” Dr. Wieben says. “So there’s a lot of positivity that comes out of this kind of testing and understanding the results.”
Now that they have their answer, the family says they feel validation and relief.
“It didn’t bother me to learn there is a connection. In fact, it felt good to be validated in that,” Deborah says. “We knew there had to be something there, because all four of us had the same problems.”
For Rylie, the results also brought a sense of comfort. “I feel better that all of our doctors now have this additional knowledge and insight,” she says. “I feel like they’re now better prepared, and that makes me more comfortable. It also makes me feel good to be able to talk to them about this.”