By Cory Pedersen
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 offers 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 Neville 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?'"
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 Barbara Domaille, a great-grandmother, the condition eventually led to the need for hip replacement surgery, as it did for her daughter, Deborah Neville.
"I have actually had both of my hips replaced," Deborah Neville says.
Deborah Neville's daughter, Pamela Neville, 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," Pamela Neville says.
Rylie, the youngest of the women and Pamela Neville'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," Pamela Neville 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.
During the course of treating each family member for their respective hip problems, Rafael Sierra, M.D., their Mayo Clinic orthopedic surgeon, began to wonder if their shared condition was not due to bad luck, but rather altered genes. Dr. Sierra thought his theory could be worth exploring further.
"Dr. Sierra 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," Pamela Neville 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. This diagnostic genetic test 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."
Barbara, Deborah Neville, Pamela Neville and Rylie had their testing done at Mayo Clinic's Genomics Core Facility in Rochester. When the results came back, Cody Wyles, M.D., an orthopedic surgery resident and Dr. Sierra's co-investigator, 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, Ph.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.
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 Neville 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."
This story first appeared on the Mayo Clinic Laboratories blog.
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Tags: genetic testing, genomic medicine, Multi-omics, Precision Medicine, Research