Gene Scene Blogs

With the GGC-MUSC membership agreement finalized earlier this year, several working groups have begun addressing joint initiatives between the two organizations. Under the initial plan of the membership agreement, five working groups have been established with joint leadership and membership from both GGC and MUSC.

“The initial stages of these working groups have been productive, and we are working to build relationships and strengthen connections across the GGC and MUSC,” said Steve Skinner, MD, Director of GGC. “We are excited about the progress and plans of each group to improve access to genetics care for patients and families across SC and to strengthen both of our organizations.”

Workgroup A, led from GGC by Mike Lyons, MD, Director of Clinical Services, is tasked with increasing access to genetics services. This group’s initial goals are focused on improving access to care by coordinating referrals and appointments, more efficient use of genetic counselors, and expanding the use of telemedicine, including eConsults and eVisits. This workgroup is also coordinating workforce recruitment and utilization across both institutions.

Workgroup B, led from GGC by Mike Friez, PhD, Director of GGC’s Diagnostic Laboratories, is working toward aligning and optimizing laboratory testing with the goal of retaining genetic testing in SC by increasing laboratory referrals to GGC and improving patient and provider access to genetic testing at both institutions. This workgroup is working to reduce the costs of genetic testing and improve the ease of ordering testing for providers.

Dr. Friez also leads Workgroup C which is tasked with investing in innovative approaches to clinical delivery, genetic testing, and research. This team is driving collaboration to strengthen the use of shared technologies and key expertise, as well as developing new tests and products to support patient care.

Workgroup D, headed by Paul Pridmore, GGC’s Chief Operating Officer (COO), seeks to optimize processes such as electronic medical records, reporting capabilities, billing, and other supportive processes to increase efficiencies and decrease costs. Kevin Farren, GGC’s Director of Data Integration and Management, is leading the effort from GGC to integrate electronic medical records and laboratory information management, a critical first step in increasing efficiencies in genetic services.

Workgroup E consists of the Joint Operating Committee which includes Skinner, Pridmore, and Brandi Buff, GGC’s Chief Financial Officer (CFO), along with MUSC Health’s CEO, Pat Cawley, MD; CFO, Lisa Goodlett; and COO, Tom Crawford, PhD. This committee is tasked with providing resources and operational support to enable the success of the workgroups and to ensure the sustainability of the initiatives from the workgroups.

“Throughout the early months of our work together, we have seen wonderful collaborations between GGC and MUSC faculty and among our newly-appointed board members,” added Skinner. “The possibilities for the growth and improvement of genetics services are significant, and patients and families across SC will reap the greatest benefits.”

Photo: First meeting of the new GGC Board of Directors  L-R Seated: Dell Baker and Holisa Wharton, PhD; Standing Chris Przirembel, PhD, Steve Skinner, MD, Jay Nexsen, Charles Schulze, John Miller, Bill Stevens, Howell Clyborne, Terri Barnes, and Pat Cawley, MD. Not pictured (joined virtually) Fritz Butehorn, MD, Richard Christian, MD, and Reid Conrad.

The Division of Research at GGC is tasked with asking, and then answering, some of the most challenging questions in biology.

“The questions are often posed to us by our colleagues in the clinical and diagnostic lab divisions when they identify a patient with atypical symptoms or find a novel or unusual genetic variant,” said Rich Steet, PhD, Director of Research at GGC, pictured below. “It then becomes our job to try and figure out how the gene variants in question cause the symptoms that they do. Once we
get to the ‘how this happened’, we have a better sense of the possible ways the condition may be treated.”

Steet and his research team recently collaborated with colleagues at the University of Georgia (UGA), Johns Hopkins School of Medicine, and Children’s Hospital Colorado, on another ‘how’ for two GGC families who have a genetic variant in the gene ALDH18A1. Variants in this gene are known to cause a spectrum of disorders that include skin and neurological findings. ALDH18A1 has also been implicated in several human cancers including breast cancer and melanoma.

In one GGC family, a ten-year-old girl with significant developmental delay, neurologic issues and gastrointestinal concerns, was found to have the new variant. In another family, three siblings who all have the gene variant, exhibit developmental delays, growth issues, loose skin, and gastrointestinal symptoms.

“At this point, all that we can do to treat these children has been to manage some of their symptoms,” said Mike Lyons, MD, Director of Clinical Services at GGC. “If we can understand how the underlying disease is caused by the genetic changes, we have a better chance of intervening at the most basic level and improving their overall health and  development.”

Steet and colleagues used skin cells from one of these four patients to, first of all, confirm that these new variants that were identified were truly disease-causing. “Using cell-based experiments, we were able to show that these genetic variants impact the function of the enzyme encoded by the ALDH18A1 gene,” said Steet, “but that work did not provide any insight about how the genetic change was causing the specific symptoms seen in the patients.” For that, the team explored how the enzyme that is encoded by this gene, P5CS, was altering the metabolic and transcriptional program of the patient’s cells.

“Our colleagues at UGA looked at the metabolomic profile which is basically a large-scale study of all of the small molecules or metabolites with the cell,” said Steet. “What we found is that the defective enzyme was affecting numerous metabolic pathways that had not been identified in prior studies.”

When the P5CS enzyme is impaired, as it is in these two families, there is a reduction in several metabolites, including a key component of collagen, which Steet said may explain the loose skin findings, and an antioxidant molecule called glutathione which helps protect against oxidative damage and may explain the neurological symptoms.

The researchers also looked at gene expression effects using RNA sequencing, uncovering other sensitive pathways that may contribute to the skin and neurological findings in these children.

“The data from this project point to the involvement of antioxidant responses in the disease process,” said Steet. “We believe that antioxidant supplementation, or drugs that boost the production of antioxidant molecules, may be a possible therapeutic avenue.”

Further studies on cells and animal models to test this hypothesis will be needed before any treatment plan for patients can be considered.

This work was published online in September in advance of print publication in the journal, Human Molecular Genetics.

 

Top photo: Tonya Moss, research technologist and coauthor on the paper, loads a Western blot to analyze the P5CS enzyme encoded by the ALDH18A1 gene.

Bottom photo: Sneha Mokashi, PhD, a postdoctoral associate in the Steet lab and coauthor on the paper, reviews gene expression data for ALDH18A1.

JT Shorter loves to run.

And he’s very good at it. That was evident with his first place finish at GGC’s 12th annual Race the Helix-Greenwood, held during GGC’s Gene Week festivities in October.

But this wasn’t the first time that JT had been to GGC. His first visit was at age nine when he was referred for a genetics evaluation following his diagnosis of autism spectrum disorder.

“We suspected that James Thomas (or JT as he likes to be called at school), might be on the spectrum around age 3 or 4,” said his father, KJ Shorter. “He was always very verbal and does well academically, so it can be difficult for some to understand that he has this diagnosis, but he has social struggles, anxiety, and sometimes might appear rude when he doesn’t mean to be.”

His parents shared that JT has learned to deal with some of these struggles through ABA, or Applied Behavioral Analysis therapy at Project HOPE Foundation in Greenwood, and he is thriving at Thornwell Charter School in Clinton where he runs on the cross country team.

“His school has a wonderful faculty and staff who understand that all children are different, and they meet them where they are,” said KJ.

JT was only able to run one meet during his first year of cross country because of COVID, but he ran in 8th grade and again this year as a high school freshman.

“Running has been wonderful for him,” said his mother, Kristen. “It has further developed his social skills, and he’s becoming a leader on the team by encouraging his teammates. It also helps to manage his excess energy.”

The Shorter family are regulars at Race the Helix events. They served as the host family for the 2018 Greenwood race, presenting the awards and sharing their family’s GGC experience with JT, his 8-year-old brother, Knox, and six-year-old brother, Elias, all of whom are GGC patients.

“We are very thankful for the Greenwood Genetic Center and want to let people know about the wonderful resource we are blessed to have in our state,” added KJ.
The Shorters are also close friends with the Shenal family who started Race the Helix in 2010. Ryleigh Shenal was one of Knox’s first friends when he started therapy at 6 months, and ‘he was always so excited to see Ryleigh every time he went to therapy,” said Kristen.

“The passion that the Shenals share about the Greenwood Genetic Center with all who will listen is inspiring, and we genuinely wanted to be part of the race,” added Kristen.
Race the Helix – Greenwood is in its 12th year of raising awareness and funds to support GGC. All proceeds from this year’s event benefit the GGC Foundation’s ‘GGC Cares Fund’ which helps offset the cost of genetic testing for patients who are uninsured or under insured.

“The 2022 event was our largest Race the Helix ever,” shared Cady Nell Keener, CFRE, Executive Director of the GGC Foundation. The Greenwood race attracted over 320 participants, both in person and virtually, and raised over $50,000 in sponsorships.

One of the presenting sponsors, Bionano, a provider of genome analysis solutions based in San Diego not only sponsored the race, but they also held their own Race the Helix event in California for employees to participate together. Bionano President and CEO, Erik Holmlin, PhD, and Chief Medical Officer, Alka Chaubey, PhD, even flew to Greenwood to participate in person with Holmlin winning his age group.

“We are so grateful to all of the participants, volunteers, and generous sponsors who made this event such a success,” added Keener.

With a nationwide shortage of clinical geneticists and genetic counselors, clinics must get creative to manage the demand for genetic services and avoid long wait times for appointments. One way that GGC and other genetics organizations are addressing this workforce shortage is through the addition of a new professional – the genetic assistant.

Genetic assistants (GAs) typically have a bachelor’s degree in a health-related or scientific field and support geneticists and genetic counselors by managing administrative tasks in the clinic setting. They assist with referrals, scheduling, sample coordination, and billing activities associated with patient visits. GGC currently employs four genetic assistants, one each in the Center’s Greenwood and Greenville locations and two in the Charleston office.

 Alli Davis joined GGC’s Charleston office in 2021 as a genetic assistant in the metabolic clinic where she assists with tasks such as scheduling, coordinating testing, requesting insurance authorizations, and creating genetic lectures.

“One of the things I love most about being a GA is having the opportunity to directly impact a patient and their family’s experience with GGC,” shared Davis. “I have had the pleasure of meeting many unique and wonderful patients and families during my time at GGC!”

In metabolic clinics, many of the patients are followed and treated long term, which is something Davis enjoys about her role. “It is wonderful to watch the patients grow and thrive throughout the years we see them.”

GAs at GGC have also become involved in implementing workflows for eConsults and eVisits.

“GGC was awarded a grant from The Duke Endowment to develop a program to improve access to genetic services by having GGC providers communicate asynchronously with non-genetics providers (eConsults) and with our patients (eVisits),” said Mike Lyons, MD, GGC’s Director of Clinical Services. “Part of that grant specifically covered the addition of genetic assistants. Our GA in Greenwood, Mattie Piotrowski, has been a critical part of the development of this innovative approach to genetics care.”

Piotrowski has helped to create the workflows for eVisits, which are offered to patients who are due for a follow-up appointment.

“eVisits allow the patient to connect with their provider through a secure online platform at their convenience,” said Piotrowski “They can check in, get their questions answered, and if recommended, we can even coordinate additional genetic testing through this platform.”

One of Piotrowski’s main roles has been to educate patients on the availability and benefits of eVisits.

“Once I explain how eVisits work and the convenience of not having to travel or wait for an appointment, we have had many follow-up patients complete eVisits with great success,” Piotrowski explained. “This also opens up appointments for new patients or those who prefer or need in-person care, reducing their wait times.”

With the growing impact of GAs on GGC’s patient care, GGC’s Division of Education has partnered with Lander University’s School of Nursing to develop a Genetic Health Studies certificate program to prepare students to work as a GA in a genetics clinic.

Holisa Wharton, PhD, Dean of the William Preston Turner School of Nursing at Lander and a member of GGC’s Board of Directors, worked closely with Leta Tribble, PhD, GGC’s Director of Education to develop the curriculum.

“The certificate program at Lander is co-taught by Lander nursing faculty and GGC faculty. The five course sequence covers topics such as pedigree construction and analysis, laboratory testing, and genetic treatments,” said Tribble. “Students also have the opportunity to complete a rotation at GGC to observe in clinics and practice skills to assist with patient care.”

“The skills and experience that GAs acquire in patient care settings also makes them well suited to advance their education in genetic medicine,” added Tribble. “Several previous GAs at GGC have moved on to graduate programs in genetics or genetic counseling.”

Davis and Piotrowski both became genetic assistants to gain exposure to clinical genetics with plans to pursue careers as genetic counselors.

“One of the biggest reasons why I chose to become a part of the GGC family was their commitment to promote compassion and care for patients and their families,” added Davis.

It was December 3, Phenylketonuria (PKU) Awareness Day, in 2018 when Jeremy and Dianna Puskas of Greenville, SC got the call that would change their lives forever – their adoption agency had a match! A two-year-old boy in China was in need of a home, but he had been diagnosed with PKU, a metabolic disorder, and the agency suggested that they consult with a specialist before moving forward with the adoption.

The Puskases were referred to GGC’s metabolic clinic where children and adults with PKU are treated and followed by a team of experts in metabolic disorders. Dr. Neena Champaigne met with the prospective parents. “She was so good at answering our many questions and helping us feel like we could manage his needs,” recalls Jeremy.

Individuals with PKU are unable to make an enzyme called phenylalanine hydroxylase (PAH) which metabolizes proteins from the diet, specifically the amino acid phenylalanine (phe). The treatment for PKU, which is generally identified through newborn screening, includes a restricted diet that is low in protein, especially phe.

“Elevated phe levels can be very detrimental, especially for young children,” said Meaghan Bade, RN, a nurse in GGC’s metabolic clinic. “If left undiagnosed or untreated, high phe levels can cause growth issues, seizures, and significant developmental and intellectual disabilities.”

“All we knew when we brought Levi home was what he had been eating, which was not standard fare for PKU, and his recent phe levels,” added Jeremy. “We knew nothing else about his medical history.”

Once Levi joined his new family and was under the care of GGC’s metabolic team, they noticed that his blood work didn’t fit with the typical PKU patient. Additional testing revealed that Levi didn’t actually have PKU, but a similar disorder called 6-PTPS deficiency. By getting to the correct diagnosis, Levi’s treatment changed allowing him to consume a normal diet and manage his disorder through medication alone.

“Once we had the right diagnosis and were able to start a more normal diet, there was a huge improvement in Levi’s mood,” said Dianna. “It’s amazing how much happier two-year-olds are when they aren’t hungry!”

Levi was also experiencing mild developmental issues when he first came to GGC, but through careful monitoring and his medical management, he is thriving. “It was like parts of his brain turned on for the very first time,” added Dianna.

In the early days of the pandemic, when employees were feeling disconnected, Dianna’s colleagues at Edward Jones in Greenville decided to come together for a service project which has evolved into a regular quarterly event. Dianna started a fundraiser for the group with all proceeds benefitting Race the Helix-Upstate.

“I’m so grateful for the support we have received from GGC. Even before we were technically ‘patients,’ they gave us the confidence and knowledge to adopt this extra-special boy,” said Dianna. “They didn’t take his diagnosis at face value, and instead went the extra mile to find his correct diagnosis which is the only reason his brain now works the way it should.”

“Levi is funny, kind, and adventurous,” added Dianna. “He wants to be a ‘fireman who rides a motorcycle into space’ when he grows up, and he loves running, like his dad. And as much as he likes to win, he also likes to celebrate who ‘won next.’ He was right at home at Race the Helix!”

The funds raised by Dianna and her colleagues for Race the Helix-Upstate support the GGC Cares Fund providing coverage for vital genetic testing for patients who are uninsured or underinsured.

“Any time we have an issue, all I have to do is tell GGC, and they take care of it. It’s like magic! Levi would not be where he is today, either with his health intact or even as a part of our family, without GGC.” – Dianna Puskas

After cancelling the 2020 race and holding the 2021 event virtually, the GGC team was excited to be back in person for Race the Helix-Upstate this year. The 8th annual event was held on April 30 at Conestee Nature Park in Greenville, SC.

“Our wonderful team of volunteers, generous sponsors, and enthusiastic participants made my first Race the Helix such an amazing experience,” said Cady Nell Keener, Executive Director of the GGC Foundation. “It was a thrill to meet several GGC families, like Levi’s, who shared such wonderful stories about the care they receive at the Center.”

Brooks Connor, mom to Charlie, 13, who has been followed by GGC since he was a newborn, agreed. “When Charlie was diagnosed with isovaleric acidemia at five days old, he was the only child in South Carolina with that diagnosis. We felt so alone. But once we connected with GGC, we knew we were not alone. They have been there every step of the way to support not only Charlie, but our whole family.”

The Connors have been the host family for Race the Helix-Upstate since its inception – sharing their GGC story and participating in planning the event. “We love being part of Race the Helix to help support the work of this amazing place. We call our GGC team ‘Charlie’s Angels’ because that’s what they have been to our family,” added Brooks.

Race the Helix started as the idea of another family who wanted to do something to give back to GGC after their daughter’s diagnosis.

Ryleigh Shenal, 11, was diagnosed at GGC shortly after birth with a rare deletion of part of chromosome 1. Ryleigh’s mom, Jodi recalls, “I’ll never forget the feeling when Dr. Skinner called to tell us the results of the genetic testing. We were frightened, worried, and had no idea where to turn next. Then he said ‘Remember. Ryleigh is the same beautiful baby she was before this call.’ Those words have stayed with me through all of these years, and we are eternally grateful for all that GGC has done for our family.”

Out of that appreciation, Race the Helix was born. The Shenal family planned the first event in Greenwood in 2011 with the hope of raising awareness of genetic disorders and funds to support GGC’s work.

“Now, 12 years, 21 races, and hundreds of thousands of dollars later, Race the Helix is still having a tremendous impact on GGC and the patients and families we serve every day,” added Keener.

The next Race the Helix will be held in Greenwood on Saturday, October 8. 2022. Learn more and register here.

Lysosomes are often described as the recycling centers of the cell. They are membrane bound structures within each cell containing digestive enzymes that, among other functions, break down waste products. When those enzymes are not produced due to a genetic mutation, or when the broken down molecules can’t get out of the lysosome, this leads to storage of harmful substances inside the lysosome leading to the aptly named, lysosomal storage disorders.

There are numerous types of lysosomal storage disorders (LSDs), each characterized by the type of lysosomal enzyme that is deficient, and they are of great interest to GGC researchers.

Rich Steet, PhD, GGC’s Director of Research, has spent years studying the function of lysosomes and how their abnormal function results in the clinical features associated with LSDs. While the clinical features vary between different types of LSDs, common findings include coarse facial features, cardiac and skeletal anomalies, learning difficulties, and a shortened life span.

To continue this groundbreaking work, Steet and co-principal investigator and GGC’s Director of Functional Studies, Heather Flanagan-Steet, PhD, have recently secured a four-year renewal of their long-standing grant titled ‘Pathogenic Mechanisms of Lysosomal Disease.’

The grant, which is administered by the National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health (NIH), provides $1.2 million over four years to continue the team’s ongoing work to better understand the mechanisms behind LSDs.

The funding, which is classified as an R01 grant through the NIH, is the original and historically oldest grant mechanism used by NIH. The R01 provides support for health-related research and development that is consistent with the mission of the NIH. An R01 is for mature research projects that are hypothesis-driven with strong preliminary data and are the most competitive of NIH funding sources.

“We are excited by the potential to further unravel the mysteries of lysosomal storage disorders and… that it allows us to expand our work into patient-specific projects here at GGC.”  -Rich Steet, PhD

Prior research under this grant focused on a single disorder, mucolipidosis, type II (MLII). The research team has made significant progress in understanding how MLII symptoms develop and they have been able to successfully treat cardiac and skeletal disease manifestations in their zebrafish models. This breakthrough has fostered collaborations to advance treatment studies into a mammalian model with the ultimate goal of developing an effective therapy for patients with this rare disease.

“We are pleased that our prior work on LSDs has been so fruitful and that we are able to continue to move toward better understanding and novel treatment options for families impacted by LSDs,” said Steet.

The primary hypothesis for this new round of funding is that the mechanisms identified in MLII disease are similar across other LSDs, which could lead to novel therapies for several disorders.

The grant renewal will also allow the research team to expand their work on the NUS1 gene which came to the team’s attention through a GGC patient, Chloe.
Chloe was referred to GGC at age 12 to investigate a movement disorder that was causing tremors, seizures, and learning difficulties. Whole exome sequencing was completed, and a variant was identified in the NUS1 gene.

“Chloe’s variant had never been reported before, so we were unsure of its significance,” shared Mike Lyons, MD, GGC’s Director of Clinical Services and Chloe’s clinical geneticist. “We reached out to Dr. Steet’s lab to get their help in understanding if the variant was the cause of her symptoms.”

Through both cellular and zebrafish experiments, researchers were able to confirm that Chloe’s variant was causing her movement issues. They were also able to identify the likely mechanism and a possible therapy.

“Zebrafish that mimic Chloe’s NUS1 variant not only exhibited a movement disorder as seen through abnormal swimming patterns, but they also displayed significant accumulation of cholesterol in their lysosomes,” said Flanagan-Steet. “By using an FDA-approved small molecule, we were able to reduce cholesterol storage in the zebrafish and restore normal swimming behaviors.”

The additional funding through the grant renewal will also help the research team to refine how the storage of cholesterol in the lysosomes occurs in patients with NUS1 mutations and why it leads to the neurological symptoms and movement disorders.

“After completing 13 years of research through this grant funding, we are excited by the potential to further unravel the mysteries of lysosomal storage disorders and identify novel treatments that can help patients like Chloe and the thousands of others who are impacted by LSDs,” said Steet. “While this renewal continues to support our ongoing basic research, we’re thrilled that it also allows us to expand our work into patient-specific projects here at GGC.”