Advancing the Science

Mayo Clinic Medical Science Blog – an eclectic collection of research- and research education-related stories: feature stories, mini news bites, learning opportunities, profiles and more from Mayo Clinic.

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Thu, Feb 14 7:00am · Using brain organoids to uncover causes of neuropsychiatric disorders

Mayo Clinic and Yale University collaborated in a study published in Science to create a new model for studying neuropsychiatric disorders in early human brain development. This unique collaboration brought together Mayo Clinic’s team-based, patient-centered research with Yale researchers to discover and analyze the genetic mechanisms that may cause these disorders.

The Mayo Clinic team, led by biomedical scientist Alexej Abyzov, Ph.D., used the organoid model to analyze artificially grown cells that resemble the brain (brain organoids) to outline groups of developmental genes and regulatory elements related to the cause of autism.

Researchers know that genes implicated in neuropsychiatric disorders are active in the human fetal brain. However, systematic and comprehensive studies are hampered due to the difficulty in getting fetal brain tissue. According to Dr. Abyzov, the power of organoids is that they can be created from the skin cells of any individual.

“Using brain organoids helps to uncover the genetic underprints of these disorders and helps identify functional elements that may drive disease onset,” says Dr. Abyzov. “Our results suggest that organoids may reveal how noncoding mutations contribute to the cause of autism. By understanding the cause of autism this research may lead to assessing the personal risk for other neuropsychiatric disorders.”

The research team set out to discover gene-regulatory elements and chart their dynamic activity during prenatal human brain development, focusing on enhancers (the short region of DNA), which carry most of the weight upon regulation of gene expression.

“Over a period of time we modeled human brain development using human-derived brain organoids and compared those organoids to fetal brain tissue that had the same genotype,” says Dr. Abyzov. “This study validated that using brain organoids is a suitable model system for studying gene regulation in human embryonic brain development, evolution and disease.”

The research team is planning a larger study using organoids to compare regulation and expression during development for individuals with autism.

“This model has the potential to offer a personalized approach to each patient with autism,” says Dr. Abyzov.

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Dec 10, 2018 · Novel data-driven approach for precision medicine

Thousands of patients’ tumors have been sequenced in the past decade, yielding a rich source of data on the changes associated with the cancer development and treatment response. However, there are no validated methods that are used in the clinic to select the best therapy. Today, Mayo Clinic researchers report an omics-guided (comprehensive) drug prioritization method tailored to an individual cancer patient.

“To date, genomic sequencing data provided to clinicians includes information on a small set of gene alterations. Recommendations for therapy do not account for many other genomic and clinical factors that might dictate tumor response,” says Mayo researcher Krishna Rani Kalari, Ph.D. “Therefore, there is an urgent need for a comprehensive approach to integrate an individual’s clinical, germline and tumor genomic data to identify and select the best treatment for a patient.”

Dr. Rani Kalari, a computational biologist, and lead author of a Mayo Clinic led study, published in JCO Clinical Cancer Informatics showed that combining multiple sources of data to predict the most effective drug choices for patients with cancer is feasible.

“We developed PANOPLY- Precision cancer genomics report: single sample inventory, an open-source computational framework to analyze complex multidimensional data to determine the most appropriate drug to target an individual’s tumor,” says Dr. Kalari. “PANOPLY approach is more comprehensive and efficient than existing single-sample analyses methods,” says Dr. Kalari.

PANOPLY includes existing FDA-approved drugs and prioritizes the drugs for patients with cancer-based on their omics profile and reports the results for oncologists to guide treatment decisions. In this study, PANOPLY was applied to in-house breast cancer datasets, and the findings were confirmed with patient-derived xenograft (PDX) models Tissues or cells from a patient’s tumor are implanted into an immuno-deficient mouse. These mouse models are used to create an environment that resembles the natural growth of cancer, for the study of cancer progression and treatment. In addition, the researchers demonstrated the flexibility of the PANOPLY framework by applying it to colon, breast, ovarian and glioblastoma datasets from The Cancer Genome Atlas.

Dr. Rani Kalari is using high-throughput tumor sequence data and teaming up with basic scientists such as Liewei Wang, Ph.D., M.D. director of the Mayo Clinic Pharmacogenomics Program, to determine whether PANOPLY can identify novel drug targets. After successful testing and benchmarking of the method using PDX repositories, they plan to work towards the ability to merge PANOPLY reports into the electronic medical records so the information is available to oncologists.

“Currently, the vast majority of patients with cancer continue to receive treatments that are minimally informed by omics data. Working with Mayo Clinic surgeon Judy Boughey, M.D. and oncologist Matthew Goetz, M.D., we anticipate that the proposed work will open new research and clinical vistas to allow a more individualized approach for the better treatment of patients,” says Drs. Kalari.

Mayo Clinic authors are:

Krishna R. Kalari, Ph.D.

Jason P. Sinnwell

Kevin J. Thompson, Ph.D.

Xiaojia Tang, Ph.D.

Erin E. Carlson

Jia Yu, Ph.D.

Peter T. Vedell, Ph.D.

James N. Ingle, M.D.

Richard M. Weinshilboum, M.D.

Judy C. Boughey, M.D.

Liewei Wang, Ph.D., M.D.

Matthew P. Goetz, M.D.

Vera Suman, Ph.D.

This study is funded in part by the Mayo Clinic Center for Individualized Medicine; Nadia’s Gift Foundation; John P. Guider; the Eveleigh Family; George M. Eisenberg Foundation for Charities; generous support from Afaf Al-Bahar; and the Pharmacogenomics Research Network (PGRN).  Other contributing groups include the U54 GM114838, Mayo Clinic Cancer Center (P30CA 15083-43) and the Mayo Clinic Breast Specialized Program of Research Excellence (SPORE- P50CA116201).

Oct 18, 2018 · What is the impact on health care of genome editing?

Although Mayo Clinic does not use genome editing as part of any treatment in the medical practice, genome editing has promise for treating and even curing previously intractable disorders, such as Duchenne muscular dystrophy.

Genome editing, via methods like CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and CRISPR-associated protein) can be used to facilitate the targeted modification of specific genes in living cells from the body and germline (inherited) sources. However, there are uncertain and potentially undesirable side effects to genome editing and regulatory oversight of genome editing is also unclear.

Genomic experts discussed the technological basis for genome editing, its current and potential research and clinical applications, and ethical and regulatory concerns at the Individualizing Medicine Conference: Advancing Care through Genomics. The Mayo Clinic Center for Individualized Medicine (CIM) hosted the conference at the Mayo Civic Center in Rochester, Minnesota.

What is gene editing?

Shondra Pruett-Miller, Ph.D.

Shondra Pruett-Miller, Ph.D., Assistant Member of Cell and Molecular Biology, St. Jude Children’s Research Hospital, spoke about the molecular biology behind gene editing and how it works, in addition to its advantages and limitations. Dr. Pruett-Miller explained gene knockout, which is a genetic technique in which one of a cell’s or organism’s genes is “knocked out” of the respective genome for the purpose of understanding the function of the gene.

“Using this technology in agriculture has huge implications from creating heat-resistant cattle to drought-resistant crops,” says Dr. Pruett-Miller.

However, there are still limitations to genome editing.  According to Dr. Pruett-Miller in order for this technology, and specifically CRISPR-Cas9, to reach its full therapeutic potential, every effort must be made to ensure that the genome edits are made with minimal chance of off-target effects on the structure of the gene.

From gene therapy to genome surgery

Stephen Tsang, M.D., Ph.D.

Stephen Tsang, M.D., Ph.D., Laszlo Z. Bito Associate Professor of Ophthalmology and Associate Professor of Pathology and Cell Biology, Ophthalmology, Columbia University, spoke about the current and potential research and clinical applications of genome editing. Dr. Tsang explored the beginnings of gene therapy and the path that led to genome surgery.

“Gene therapy is not the same as gene surgery, also known as gene-editing,” says Dr. Tsang. “CRISPR-Cas9 opened a new chapter in medicine.”

Gene therapy uses genes as a “drug” to treat or prevent disease by modifying, supplying or blocking gene expression or gene products that cause a condition either by their presence or absence.

CRISPR-Cas9 is a method of genome surgery that enables geneticists and medical researchers to edit parts of the genome by removing, adding or altering sections of the DNA sequence. Dr. Tsang used the example of juvenile macular degeneration as a perfect target for CRISPR-Cas9.

“The eye is the ideal system for genome surgery as well as stem cell transplantation: its relative immune privilege and accessibility, and the effects of treatment can be precisely monitored at the resolution of a single cells with non-invasive imaging allowing physicians to monitor what is happening in real time as they put the cell in and interact with eye,” says Dr. Tsang. “The eye is a self-contained area preventing CRISPR off-targeting from going to other parts of the body. As a pair organ, the eye provides the ideal treatment-control conditions and distinguishes itself as the ideal system for Individualized Medicine due to the low risk of off-targeting of genome surgery and stem cell therapies.”

The science has to advance first

Megan Allyse, Ph.D.

Megan Allyse, Ph.D., Assistant Professor of Biomedical ethics at Mayo Clinic closed the session discussing ethical and regulatory concerns related to genome editing and how they may impact clinical decision-making.

According to Dr. Allyse with the advent of gene therapy and gene surgery the National Academy of Sciences laid out clear guidelines relating to responsible science.  The National Academy of Sciences covers all facets of responsible science from transparency, respect of the person, fairness, to due care (proceeding carefully and deliberately and only when supported by sufficient and robust evidence).

“Although we have a lot of structures in place to monitor gene editing there are many unresolved dilemmas,” says Dr. Allyse.

Dr. Allyse posed several thought provoking questions to the audience concerning the ethical and regulatory issues such as:

  • “Who defines what a serious condition or disease is?”
  • “How do you handle illegitimate stem cell therapies and the exploitation of people who are desperate to solve a health issue?”
  • “Is the human genome sacred?”

The questions set up a hard conversation with those in attendance and the answers were as varied and individual as each person.

“As much as we want to get into humans, the science has to come first,” says Dr. Allyse. “Our goal is to bring people up to health as opposed to pushing them to enhancement.”

Keep the conversations going

For more information on the Mayo Clinic Center for Individualized Medicine, visit our blogFacebookLinkedIn or Twitter at @MayoClinicCIM.

Apr 19, 2018 · Direct-to-consumer genetic testing-a rapidly shifting landscape

Direct-to-consumer genetic or over the counter testing emerged in the early 2000s as a means of allowing consumers to access information about their genetics without the involvement of a physician. While early models were popular with consumers, they were controversial in medical and regulatory circles.

In the January 2018 issue of Mayo Clinic Proceedings authors Megan Allyse Ph.D., David Robinson, Matthew Ferber Ph.D. and Richard Sharp Ph.D. trace the history of direct-to-consumer genetic testing, discuss its regulatory implications, and describe the emergence of a new hybrid model.

Direct-to-consumer testing — the early days

Megan Allyse, Ph.D.

In 2007 the journal Science named human genetic variation the “breakthrough of the year” and direct-to-consumer companies were offering microarray panels for $1,000. Fast forward five years and the curious consumer could get a microarray panel for $99. Microarray refers to a microchip-based testing platform that allows high-volume, automated analysis of many pieces of DNA at once.

“Consumers liked the convenience of direct-to-consumer testing, the appeal of gaining access to their personal genetic information, and its promotion of preventive and individualized medicine,” says Dr. Allyse, a Mayo Clinic bioethicist, and lead-author of the paper.

However, critics quickly raised concerns about direct-to-consumer testing.

  • Risk of misinterpreting genetic test results
  • Making health decisions on inaccurate or incomplete information
  • Lack of consideration for ethnic and racial differences across human populations
  • Potential for unnecessary, expensive, or time-consuming downstream medical testing
  • No clear regulatory mechanisms in place to assess the analytical and clinical validity, and clinical utility
  • Poor procedures in place to ensure informed consent for the testing process
  • Consumers may not understand the health implications of the information they received
  • Companies could sell aggregate data to third parties or use consumer’s data for research without their awareness

By 2011 the government began cracking down on the practices of direct-to-consumer testing companies. In 2013, the U.S. Food and Drug Administration (FDA) ordered 23andMe to immediately discontinue marketing and sales of its health-related testing services until they received FDA authorization for these devices.

A new model emerges — direct-to-consumer 2.0

In 2015, 23andMe received FDA device approval for its carrier screen for hereditary Bloom syndrome. The FDA confirmed that 23andMe had submitted evidence demonstrating that members of the public were capable of correctly interpreting the test report at a 90 percent comprehension level.

“At the same time the FDA announced that it would classify direct-to-consumer genetic carrier screens as lower risk devices. This opened the way to testing for additional autosomal recessive conditions and signaled the FDA’s willingness to consider at least some forms of direct-to-consumer medical testing under the regulations,” says Dr. Allyse.

That same year Illumina one of the largest providers of genomic sequencing in the U.S. launched Helix, a personal genomics platform that utilizes a “sequence-once-query-often” model. Helix stores genomic information in a central database and allows its partners to develop various testing strategies that interrogate portions of genomic datasets for its customers. In 2017, the FDA approved the marketing of the first direct-to-consumer test for genetic health risk, 23andMe’s Personal Genome Service, which tests for 10 diseases or conditions, including Alzheimer’s risk, Parkinson’s disease, and hereditary thrombophilia.

“These emerging models of direct-to-consumer genetic testing attempt to strike a balance between the need to ensure consumer safety and the knowledge that personal genomic information is both highly desirable and potentially beneficial to some consumers,” says Dr. Allyse.

The future of direct-to-consumer testing 

Dr. Allyse and colleagues speculate on several promising strategies to align the interests of the direct-to-consumer market and the practice of medicine:

  • Improve pre-test education to facilitate the kind of informed consent expected in a medical setting
  • Separate consent to receive testing by purchasing a product from agreeing to the storage, use or sale of samples for research
  • Create clearer pathways into the medical system in the event of high-risk results by partnering with licensed medical providers to ensure information integrity
  • Provide a supportive environment for consumers acknowledging the entertaining nature of genetic information and provide for counseling and follow-up

The Mayo Clinic Center for Individualized Medicine continues to seek ways to apply the latest genomic, molecular and clinical science to personalized care for every individual, so patients receive the exact care they need — when they need it — and to address unmet needs of the patient.

Disclosure: The authors have no personal financial relationships to disclose. Mayo Clinic holds a commercial interest in Helix. There was no relationship between Helix and the contents of this paper.

Mayo Clinic Proceedings Symposium on Precision Medicine 

This paper is part of the Mayo Clinic Proceedings Symposium on Precision Medicine, a series of articles that cover a wide range of topics in personalized medicine. Watch for an upcoming article in the symposium focusing on how personalized medicine and genomics are impacting patient care in the area of heritable cancers.

Read more about the ethical issues of home DNA kits

Learn more about biomedical ethics

Apr 10, 2018 · New international practice guidelines for using tamoxifen to treat breast cancer

An international group of clinicians and scientists representing the Clinical Pharmacogenetics Implementation Consortium (CPIC) published the first-ever clinical practice guideline for using CYP2D6 genotype to guide tamoxifen therapy in Clinical Pharmacology and Therapeutics.

Tamoxifen is a hormonal agent used for the prevention and treatment of premenopausal and postmenopausal breast cancer that is estrogen receptor positive. CYP2D6 genotype is an inherited factor that alters the metabolism of tamoxifen.

“The goal of the CPIC Guideline for CYP2D6 and tamoxifen therapy is to provide clinicians information that will allow the interpretation of clinical CYP2D6 genotype tests so that the results can be used to guide prescribing of tamoxifen when genotype information is available,” says Matthew Goetz, M.D., a Mayo Clinic medical oncologist, who is the lead author. “The consensus of the consortium tamoxifen group was that there was sufficient evidence to use CYP2D6 genotype to assist with clinical recommendations for women who are being considered for tamoxifen for early stage estrogen receptor positive breast cancer.”

Matthew Goetz, M.D.

Tamoxifen is converted through the process of liver metabolism into forms that result in greater anti-estrogenic potency and anti-tumor activity than the parent drug. Antiestrogens are a class of drugs which prevent estrogens from mediating their biological effects in the body.

“The work of the consortium is an example of Mayo’s commitment to taking a comprehensive, collaborative team science approach to deliver advanced genomic medicine to our patients. We work with other academic medical centers, hospitals, and clinics to bring the latest discoveries to improve the practice of medicine.” – Matthew Goetz, M.D.

“The work of the consortium is an example of Mayo’s commitment to taking a comprehensive, collaborative team science approach to deliver advanced genomic medicine to our patients. We work with other academic medical centers, hospitals, and clinics to bring the latest discoveries to improve the practice of medicine,” says Dr. Goetz.

Jan 30, 2018 · How does a genomic tumor board impact patient care?

The outcomes from a Mayo Clinic study published in Oncotarget found value in having an established genomic tumor board, and using genomics for certain patients.

The experience of the Genomic Tumor Board has promoted an evolution in the practice according to Alan Bryce, M.D., a Mayo Clinic oncologist, and co-first author on the study.

“There is an emerging consensus to begin genomic analysis early in the treatment course due to many driver mutations presenting early in the disease course. This allows time for potential therapies in a clinically useful timeframe,” says Dr. Bryce.

Alan Bryce, M.D.

Mayo researchers looked at initial results from their efforts in establishing the Mayo Clinic Genomic Tumor Board. The board brings together physicians, research scientists, cancer biologists, ethicists, pathologists, bioinformaticians and genetic counselors from Mayo Clinic campuses in Arizona, Florida, and Minnesota. This “A” team reviews and discusses each case, bringing their unique expertise to the table. Through consensus they conclude if findings are deemed actionable, lead to treatment recommendations, and are deemed informative.

According to Jan Egan, Ph.D., a Mayo Clinic research scientist and co-first author, the Genomic Tumor Board provided a translational platform to transform the practice.

“We brought together the unique perspectives of clinicians and laboratory scientists to drive treatment decisions and create patient focused research questions,” says Dr. Egan.

Jan Egan, Ph.D.

The Mayo Clinic Genomic Tumor Board engaged in patient case review to address limitations by considering genomic testing results, in addition to treatment options such as: surgery, ablation, radiation, new chemotherapy, or observation. Other benefits included facilitating collaboration between physicians and scientists to assist with target prioritization or consideration of alternate targets. It also provided a forum for teaching and consideration of alternative treatment options in complex cases. The Genomic Tumor Board contributed to the ongoing revolution of tumor genomic-based treatment in cancer, along with innovations in clinical trial design, technological innovations in big data management, and regulatory changes promoting data.

What are the barriers to delivery?

The study revealed these barriers to implementing genomics into cancer care:

  • Knowledge. Fewer than half of Mayo oncology faculty, fellows and advanced practitioners surveyed felt confident enough in their understanding of genomics to make treatment recommendations and explain it to patients. The majority sought input from colleagues or conducted a literature search when uncertain.
  • Access. Patients struggle with gaining access to the recommended therapy, pointing to drug access barriers that prevent optimal use of tumor genomic testing.
  • Cost. Out of pocket expenses and reimbursement varies by insurance company.

Looking ahead, researchers identified the importance of rapidly sharing insights gained from successful treatment to other clinicians and investigators. In addition, cross-institutional databases linking genomic profiles and treatment outcomes are needed given the rarity of specific abnormality/tumor combinations. Lastly, cost of tumor sequencing should be compared to the cost of treating with unselected therapies or enrolling in non-biomarker based clinical trials.

“We demonstrated treatment decisions driven by tumor genomic analysis can lead to significant clinical benefit in a minority of patients,” says Dr. Bryce.

Jan 23, 2018 · Study evaluates effectiveness of deep genomic profiling in clinical setting

Genomic profiling is used today for patients with advanced cancers to help develop new ways to diagnose and treat their disease and offer an individualized treatment plan. While gene panel testing is relatively commonplace, there are many barriers to using new and more sophisticated DNA technologies.

According to Mitesh Borad, M.D., an oncologist at the Mayo Clinic campus in Arizona, there are two key obstacles to applying advanced DNA testing to cancers.

First, this type of approach is cost prohibitive for many patients. Insurance coverage is inconsistent for whole exomes, RNA sequencing and structural genomic assays and some patients may have to pay out-of-pocket.

Second,  it takes a large multi-disciplinary team (bioinfomaticians, lab scientists, oncologists) typically found only at large academic cancer centers.

Mitesh Borad, M.D.

To better understand these obstacles, Dr. Borad and a team of researchers pursued a genomic deep dive using clinical grade testing to better understand the impact.

The study, in Nature Scientific Reports, represents one of the earliest published efforts to date of Clinical Laboratory Improvement Amendments (CLIA)-enabled integrated deep genomic profiling for the identification of therapeutic targets in patients with advanced cancer.

The researchers pursued three objectives:

  1. Determine how much time it takes to complete integrated whole exome/long insert whole genome/transcriptome sequencing.
  2. Estimate how much time it takes to report results of therapeutically relevant drug targets derived from integrated whole exome/long-insert whole genome/whole transcriptome sequencing, along with CLIA validation.
  3. Determine process of drug access.

As a result of the study, researchers determined integrated genomic profiling in a CLIA enabled workflow was successfully demonstrated in a consistent fashion in patients with complex disease diagnosis.

“It is anticipated that with development of faster sequencing, better informatics tools and automation and drop in costs (e.g. recent announcement of potential for a $100 genome) that this will become more broadly applicable and the work presented in the study along with other complementary efforts in the field will lay a groundwork for future activities,” says Dr. Borad.

The study also provides a contextual framework to incorporate other genomic analyses into the workflow as therapeutics using these approaches enter the clinic and their role in therapeutic response prediction is better defined.

This study was supported by: NIH/NCI 1DP2CA195764, and the Mayo Clinic Center for Individualized Medicine. Dr. Borad has been involved in implementation of genome wide assays into molecular profiling efforts in early phase studies since 2007.

Sep 19, 2017 · CARING FOR KARTER--Genetic sleuths never give up hunt to identify Minnesota boy's condition

Mayo Clinic’s functional genomics team never gave up hunt to identify Karter Malcomson’s rare condition.

Karter Malcomson coos and swivels his head when he hears his name in his mother’s reassuring voice.

“You know we’re talking about you, don’t you?” Karter’s mom, Kerrie, says. “Karter is a very happy boy. He’s very content. He’s very interested in everything, especially people. He’s definitely a people person.”

His father, Zane, spins Karter upside down on his lap and smiles ensue.

“Kerrie always says how much Karter loves me,” Zane says. “I notice it when I come home from work and he reaches out to me and wants me to hold him. We have a great bond.”

Karter just turned 2 but is delayed in growth and cognitive abilities. He also has a surgically made hole in the front of his neck into his windpipe to aid in breathing.

“He’s obviously very small, the size of a 6- or 8-month-old, and he doesn’t walk. He doesn’t do any of that normal 2-year-old stuff,” Kerrie says.

PREPARING FOR KARTER

Kerrie and Zane knew before Karter was born at Mayo Clinic in Rochester, Minnesota, he would have health concerns. Karter had stopped growing in the womb and was growing extra fingers, a sign of a genetic disorder. He spent three months in the newborn intensive care unit.

As Karter began his life, his parents worried.

“Before his diagnosis, the wondering was the worst — when you just don’t know. You’re like, ‘How do I help my child? I don’t know what I’m doing. I don’t even know what he has,'” Kerrie says.

But Karter’s symptoms didn’t place him in any well-defined rare disease category. Even at an institution that sees more than 1.3 million people each year across a wide spectrum of complex conditions, his doctors realized that there was something different about Karter’s rare genetic disorder.

The Mayo Clinic Department of Clinical Genomics consults with physicians who treat patients like Karter, whose case was handled by clinical geneticist Pavel N. Pichurin, M.D. Dr. Pichurin and his colleagues try to determine the genetic disorder and provide patients with a diagnosis through review of scientific literature and tests.

But what if, after all testing is complete, the symptoms that a person has don’t match up with the results, or the results are inconclusive? What happens if there is no answer? What happens to cases like Karter’s?

GENETIC QUEST FOR ANSWERS

Charu Kaiwar, M.D., Ph.D., dreads getting the question at social events: “What do you do for a living?”

“It’s not an easy answer. It would probably be an essay,” she says.

That’s because Dr. Kaiwar, a research fellow, is part of a group that reviews the cases of people who have exceedingly rare or undiagnosed disorders like Karter’s. Dr. Kaiwar is one of the members of the functional genomics team at Mayo Clinic’s Center for Individualized Medicine. The group includes a team of experts in lab science, data crunching and genetics who are all working together to find genomic-based answers to some of the most puzzling patient questions.

This often means sifting through the literature of thousands of cases and information on thousands of genetic variants in a person’s body that may — or most likely may not — be significant.

“It’s so complicated,” Dr. Kaiwar says. “But there’s so much potential here for the future.”

That quest for an answer by the staff and patients, who typically have bounced around from different specialists in other health care organizations, can become an all-consuming pursuit.

“We are usually the last resort. We could spend hours or months on it,” says research fellow Filippo Pinto e Vairo, Ph.D. “If we are not doing this, it’s almost impossible that the physician or genetic counselor can spend the time to do it.

“That’s what motivates us. We are a team that works together with different backgrounds. We know we can share experiences and learn from each other and provide something to patients.”

The team, which is reviewing about 50 cases at any given time, solves approximately 30 percent of them. And the percentage is rising.

“Many patients with an unknown genetic disorder will have spent years managing their health problems while also trying to determine what the disease actually is,” says Margot A. Cousin, Ph.D., a health sciences research fellow. “To be done hunting for the answer, it provides a lot of comfort. These patients and families are finally able to move on from the constant wonder about the cause of their disease and focus on what they might now be able to predict.”

KARTER’S CARE

Zane, Karter and Kerrie waited for Karter’s test results while Mayo Clinic’s functional genomics team investigated. The team worked to verify variants in Karter’s C2CD3 gene that were driving his disease, which physicians ultimately diagnosed as oral-facial-digital syndrome, type 14.

Nicole J. Boczek, Ph.D., was one of the leaders of Karter’s care behind the scenes for the functional genomics team. She never met the happy-go-lucky boy, but spent months working on his case.

“Karter’s testing came back with two interesting variants, both of them within the same gene: C2CD3,” says Dr. Boczek, a molecular geneticist. “Only one paper had ever been published regarding this gene related to disease. It overlapped pretty well with Karter’s symptoms. But we had to take these findings to the next level and prove these variants of uncertain significance were related to Karter’s symptoms.”

To do that, Dr. Boczek and the team did additional laboratory testing to show that these genetic variants were affecting protein development and driving Karter’s disease. Through the team’s work, they homed in on a diagnosis — oral-facial-digital syndrome.

Oral-facial-digital syndrome has at least 13 types, according to the U.S. National Library of Medicine. Karter’s case didn’t fit in the other 13 categories and was diagnosed as type 14.

“There are nine individuals reported ever in the literature with this condition stemming from this gene,” says Dr. Boczek. “Since we’ve worked on Karter’s case, we now are contributing to the literature with four more cases. It is really rare, but it is inspiring.”

THE JOURNEY AHEAD

Kerrie says finding an answer to Karter’s condition has brought her peace, while Zane said he believes the information will help them in the future.

“There’s so much potential. His doctors can only guess at what he’ll be able to do, and he continues to surprise us every day,” Zane says. “It gives us hope for the future.”

Karter’s breathing, sleep and vision issues are managed by a comprehensive treatment plan. He also works with a physical therapist weekly. Kerrie raves about the compassionate care Karter and her family have received each step along the way.

“I really have grown to love the care team he has now,” Kerrie says. “I don’t have to worry.”

And Karter, who listens intently and claps intermittently to a musical toy in his living room, has proven the ability to exceed any preconceived expectations.

Kerrie and Zane hope one day Karter will be able to meet milestones such as crawling, changing positions and maybe walking. But for now, they’re happy that he’s happy.

“Karter is a happy boy, not someone with health issues,” Kerrie says. “He’s very personable. He’s everybody’s best friend.”


A RECIPE FOR UNDERSTANDING GENETIC FUNCTION

Genetics continues to be at the forefront of research, patient diagnosis and treatment. But how do each person’s genes and genetic variants factor in his or her care?

Consider the example Nicole J. Boczek, Ph.D., uses when she discusses the role of genetics:

“There are trillions of cells in someone’s body, and all of them have a copy of a ‘recipe book’ (your DNA). That recipe book helps each cell make all the different recipes to help us live our lives every single day, making each cell function, helping our hearts beat, making our digestive system work properly, and so on.

“There are typos in every person’s recipe book. A lot of times, these typos are small, maybe a word is spelled wrong, but it doesn’t change the content. Your body can still read and understand the recipe and everything is fine. But if there’s a typo at a key point, such as changing the baking temperature from 350 degrees Fahrenheit to 550 degrees Fahrenheit, this can completely change the end product and may cause a significant problem.

“So our goal is to try and find all of the typos in each recipe — or gene — and see which ones are actually important and make significant changes to the recipe to establish if there’s going to be a problem.”

THE BEGINNING OF A TEAM

In the late 1990s before he earned a doctoral degree, Eric W. Klee, Ph.D., became hooked on an emerging field of science.

Dr. Klee, from a family of medical doctors, still wasn’t sure whether to pursue an M.D. when mentor Franklyn G. Prendergast, M.D., Ph.D., told him that the future of medicine would be in a developing field of study.

“I like computers. I like technology, but I also liked medicine,” Dr. Klee says. “And Dr. Prendergast said, ‘There’s a field in science called bioinformatics. It doesn’t really exist yet, and it won’t exist for a few years, but when it does, it’s going to be important for decades.'”

Dr. Klee took the leap of faith that the numbers would work out in his favor, graduating with a Ph.D. in health informatics/bioinformatics. He joined Mayo Clinic in 2005 as one of the first employees hired with a degree based in the emerging field that applies large amounts of health data into individualized tests and treatment plans for patients.

In 2012, Mayo Clinic created the Bioinformatics Program under the direction of the Center for Individualized Medicine. The center also launched the Individualizing Medicine Conference to provide a space for collaboration aimed at better incorporating genomic information into patient care.

At the conference Dr. Klee sought out then-center director Gianrico Farrugia, M.D., and associate administrator Scott A. Beck to propose the idea of a team that could dig deep into the functional science of genetic changes on behalf of patients with undiagnosed genetic disorders. Benefactors helped the concept gain seed funding, and the functional genomics team blossomed.

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Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. This article was originally featured on the philanthropic site “You Are…the campaign for Mayo Clinic.”

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