Tag Archive for: genetics

photos used for facial analysis technology

Facial analysis technology successful in identifying Williams-Beuren syndrome in diverse populations

photos used for facial analysis technology

Image Credit: Darryl Leja, NHGRI.

In an international study led by the National Human Genome Research Institute (NHGRI), researchers have successfully identified Williams-Beuren syndrome in diverse populations using clinical information and objective facial analysis technology developed by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National.

The technology, which was featured by STAT as an ‘Editor’s Pick’ finalist in their recent competition to find the best innovation in science and medicine, enables users to compare the most relevant facial features characteristic of Williams-Beuren syndrome in diverse populations.

Williams-Beuren syndrome affects an estimated 1 in 7,500 to 10,000 people, with the most significant medical problems being cardiovascular, including high blood pressure. Though the syndrome is a genetic condition, most cases are not inherited. Signs and symptoms include intellectual disability and distinctive facial features including puffiness around the eyes, a short nose with a broad tip, full cheeks and a wide mouth with full lips.

Using the facial analysis technology, the researchers compared 286 African, Asian, Caucasian and Latin American children and adults with Williams-Beuren syndrome with 286 people of the same age, sex and ethnicity without the disease. They were able to correctly identify patients with the disease from each ethnic group with 95 percent or higher accuracy.

“Our algorithm found that the angle at the nose root is the most significant facial feature of the Williams-Beuren syndrome in all ethnic groups and also highlighted facial features that are relevant to diagnosing the syndrome in each group,” said Marius George Linguraru, D.Phil., developer of the facial analysis technology and an investigator in the study from Children’s National.

Linguraru and his team are working to create a simple tool that will enable doctors in clinics without state-of-the-art genetic facilities to take photos of their patients on a smartphone and receive instant results.

The technology was also highly accurate in identifying Noonan syndrome according to a study published in Sept. 2017, DiGeorge syndrome (22q11.2 deletion syndrome) in April 2017 and Down syndrome in Dec. 2016. The next study in the series will focus on Cornelia de Lange syndrome.

2nd-annual-hackathon

Genetic testing reigns triumphant at health app hackathon

2nd-annual-hackathon

The growing popularity of genetic testing has one large hurdle: There are fewer than 4,000 genetic counselors in the United States, and people who use commercial genetic testing kits may receive confusing or inaccurate information.

To combat this problem, a team of doctors from the Rare Disease Institute at Children’s National Health System created the framework for a smartphone application that would house educational videos and tools that provide reputable information about genetic disorders and genetic testing.

On April 13, 2018, Debra Regier, M.D., Natasha Shur, M.D., and their teammates presented the app “Bear Genes” at the 2nd Annual Medical & Health App Development Workshop, a competition sponsored by the Clinical and Translational Science Institute at Children’s National (CTSI-CN) and the Milken Institute School of Public Health (Milken Institute SPH) at the George Washington University. Bear Genes won first place, and the team received $10,000 to develop a working prototype of the app.

The Bear Genes team was one of 10 who presented their ideas for smartphone apps to a panel of judges at the competition. Ideas covered a variety of topics, including emergency room visits and seizures related to menstrual cycles. Sean Cleary, Ph.D., M.P.H., an associate professor of epidemiology and biostatistics at the Milken Institute SPH, and his teammates proposed an app called “MyCommunicationPal” that would assist autistic individuals in reporting their symptoms to healthcare providers.

Sean Cleary and Kevin Cleary, Ph.D., technical director of the Bioengineering Initiative at Children’s National Health System, created the hackathon to bring together professionals from various fields to create technology-based solutions for public health and medical challenges. Interested participants submit applications and app proposals in the fall, and 10 ideas are selected to be fleshed out at the half-day hackathon. Participants join teams to develop the selected ideas, and on the day of the event, create a five-minute presentation to compete for the top prize. About 90 people attended this year’s hackathon.

“The workshop provides us with the opportunity to collaborate with healthcare providers, public health professionals and community members to develop an appropriate user-friendly app for those in need,” said Sean Cleary. “The event also fosters future collaborations between important stakeholders.”

This article originally appeared in the Milken Institute SPH pressroom.

STAT Madness

Voters select Children’s National innovation as runner-up in national competition

STAT Madness

Facial recognition technology developed and tested by researchers with the Sheikh Zayed Institute for Pediatric Surgical Innovation and Rare Disease Institute at Children’s National was the runner-up in this year’s STAT Madness 2018 competition.

Facial recognition technology developed and tested by researchers with the Sheikh Zayed Institute for Pediatric Surgical Innovation and Rare Disease Institute at Children’s National was the runner up in this year’s STAT Madness 2018 competition. Garnering more than 33,000 overall votes in the bracket-style battle that highlights the best biomedical advances, the Children’s National entry survived five rounds and made it to the championship before falling short of East Carolina University’s overall vote count.

Children’s entry demonstrates the potential widespread utility of digital dysmorphology technology to diverse populations with genetic conditions. The tool enables doctors and clinicians to identify children with genetic conditions earlier by simply taking the child’s photo with a smartphone and having it entered into a global database for computer analyses.

The researchers partnered with the National Institutes of Health National Human Genome Research Institute and clinicians from 20 different countries to acquire pictures from local doctors for the study. Using the facial analysis technology, they compared groups of Caucasians, Africans, Asians and Latin Americans with Down syndrome, 22q11.2 deletion syndrome (also called DiGeorge syndrome) and Noonan syndrome to those without it. Based on more than 125 individual facial features, they were able to correctly identify patients with the condition from each ethnic group with more than a 93 percent accuracy rate. Missed diagnoses of genetic conditions can negatively impact quality of life and lead to premature death.

Children’s National also was among four “Editor’s Pick” finalists, entries that span a diverse range of scientific disciplines. Journalists at the digital publication STAT pored through published journal articles for 64 submissions in the single-elimination contest to honor a select group of entries that were the most creative, novel, and most likely to benefit the biomedical field and the general public.

Each year, 1 million children are born worldwide with a genetic condition that requires immediate attention. Because many of these children experience serious medical complications and go on to suffer from intellectual disability, it is critical that doctors accurately diagnose genetic syndromes as early as possible.

“For years, research groups have viewed facial recognition technology as a potent tool to aid genetic diagnosis. Our project is unique because it offers the expertise of a virtual geneticist to general health care providers located anywhere in the world,” says Marius George Linguraru, D.Phil., M.A., M.S., a Sheikh Zayed Institute for Pediatric Surgical Innovation principal investigator who invented the technology. “Right now, children born in under-resourced regions of the U.S. or the world can wait years to receive an accurate diagnosis due to the lack of specialized genetic expertise in that region.”

In addition to providing patient-specific benefits, Marshall Summar, M.D., director of Children’s Rare Disease Institute that partners in the facial recognition technology research, says the project offers a wider societal benefit.

“Right now, parents can endure a seemingly endless odyssey as they struggle to understand why their child is different from peers,” says Dr. Summar. “A timely genetic diagnosis can dispel that uncertainty and replace it with knowledge that can speed patient triage and deliver timely medical interventions.”

Rare Disease Institute director named to Global Commission to End the Diagnostic Odyssey for Children

Marshall Summar, M.D., director of the Children’s National Rare Disease Institute (CNRDI), has been named to the Global Commission to End the Diagnostic Odyssey for Children.

Children’s National Health System has announced that Marshall Summar, M.D., director of the Children’s National Rare Disease Institute (CNRDI), has been named to the Global Commission to End the Diagnostic Odyssey for Children (“the Global Commission”), an alliance dedicated to shortening the multi-year journey that rare disease patients and families endure on the road to diagnosis.

Established in partnership with Shire, Microsoft and EURORDIS, the Global Commission is comprised of a multi-disciplinary team of global experts that have the commitment, creativity and technological expertise required to make a substantial difference in the lives of the millions of children living with a rare disorder.

“Providing more help to children born with rare genetic diseases continues to be one of the core challenges of 21st century medicine,” says Dr. Summar, who notes that patients typically visit up to eight doctors and often receive two or three misdiagnoses along the way. “Even upon diagnosis, patients are hindered by scarce treatment options and approximately a third of patients die before their fifth birthday. We are committed to changing this trend at the CNRDI and are excited to have the opportunity to share our expertise with this alliance on a global stage.”

The Global Commission is focused on developing an actionable roadmap for the field of rare disease that offers recommendations to address core challenges that prevent timely diagnosis for rare disease patients, including improving physicians’ ability to identify and diagnose rare disorders, empowering patients to take an active role in their healthcare and providing high-level policy guidance to help rare disease patients achieve better health outcomes.

Beginning its work in 2018, the Global Commission expects to publish a roadmap that encapsulates the collective findings in early 2019. Over the course of the next year, the alliance will gather input from patients, families and other experts to gain key insights and develop solutions to shorten the diagnostic odyssey.

In the United States, it is estimated that one in 10 people has a rare disease – approximately 80 percent of which are genetically based. Additionally, the National Institutes of Health reports that more than 80 percent are childhood diseases and more than 25 percent of children admitted to pediatric hospitals have a rare disease.

Marshall Summar

Horizon Pharma gifts $3M to establish Horizon Pharma Clinical Care Endowment at Children’s National Rare Disease Institute

Marshall Summar

“Patients and families with rare conditions deserve to be treated in a place with the medical knowledge to provide quick, clear answers and the expert care they need,” says Marshall Summar, M.D., director of the CNRDI.

Children’s National Health System and Horizon Pharma plc are pleased to announce the creation of the Horizon Pharma Clinical Care Endowment, the first clinical team endowment at the Children’s National Rare Disease Institute (CNRDI). The endowment is made possible by a generous six-year, $3 million commitment from Horizon Pharma USA, Inc., a wholly owned subsidiary of Horizon Pharma plc –a biopharmaceutical company dedicated to improving the lives of people living with rare diseases.

“Patients and families with rare conditions deserve to be treated in a place with the medical knowledge to provide quick, clear answers and the expert care they need,” says Marshall Summar, M.D. , director of the CNRDI.  “We are grateful for Horizon and their support of our mission to make the Children’s National Rare Disease Institute that place. This endowment will support a dedicated team that can provide optimal, comprehensive care to more patients and ensure that families have a trusted source for all aspects of their health care.”

The Horizon Pharma Clinical Care Endowment will generate revenue annually, providing stable support for an expert care team at the CNRDI. Each team will be comprised of a clinical geneticist and support team members – such as genetic counselors, nutritionists and social workers – all specializing in the care of children with rare disease.

The long-term support provided by the Horizon Pharma Clinical Care Endowment will give the CNRDI a firm foundation for treating patients earlier, more consistently and over the course of their lifetime. Horizon’s commitment marks the first donor-funded endowment at the CNRDI.

Currently, it is estimated that one in 10 Americans has a rare disease – approximately 80 percent of which are genetically based. Additionally, the NIH reports that more than 80 percent are childhood diseases, and more than 25 percent of children admitted to pediatric hospitals have a rare disease.

The CNRDI is a first-of-its-kind center focused exclusively on advancing the care and treatment of children and adults with rare genetic diseases. It is the first National Organization for Rare Disorders (NORD) Center of Excellence and aims to provide a medical home for patients and families seeking the most advanced care and expertise for rare genetic conditions that remain largely unknown to the general medical community.

Eric Vilain

Exploring differences of sex development

Eric Vilain, M.D., Ph.D.

Eric Vilain, M.D., Ph.D., analyzes the genetic mechanisms of sex development to give families more answers that will help them make better treatment (or non treatment) decisions for a child diagnosed with DSD.

Eric Vilain, M.D., Ph.D., is well versed in the “world of uncertainty” that surrounds differences of sex development. Since joining Children’s National as the director of the Center for Genetic Medicine Research in 2017, he’s shared with our research and clinical faculty and staff his expertise about the ways that genetic analysis might help address some of the complex social, cultural and medical implications of these differences.

Over the summer, he gave a keynote address entitled “Disorders/Differences of Sex Development: A World of Uncertainty” during Children’s National’s Research and Education Week, an annual celebration of research, education, innovation and scholarship at Children’s National and around the world. In January 2018, he shared a more clinically oriented version of the talk at a special Children’s National Grand Rounds session.

The educational objective of these talks is to inform researchers and providers about the mechanisms of differences of sex development (DSD), which are defined as congenital conditions in which the development of chromosomal, gonadal or anatomical sex is atypical.

The primary goal, though, is to really shine light on the complexity of this hot topic, and share how powerful genetic tools can be used to provide vital, concrete information for care providers, patients and families to assist with difficult treatment (and non-treatment) decisions.

“A minority of DSD cases are able to receive a genetic diagnosis today,” he points out. “But geneticists know how important it is to come to a diagnosis and so we seek to increase the number of patients who receive a concrete genetic diagnosis. It impacts genetic counseling and reproductive options, and provides a better ability to predict long term outcomes.”

“These differences impact physiology and medicine. We want to better understand the biology of reproduction, with an emphasis on finding ways to preserve fertility at all costs, and how these variations may lead to additional complications, including cancer risk.”

At conception, he explains, both XX and XY embryos have bipotential gonads capable of differentiating into a testis or an ovary, though embryos are virtually indistinguishable from a gender perspective up until six weeks in utero.

Whether or not a bipotential gonad forms is largely left up to the genetic makeup of the individual. For example, a gene in the Y chromosome (SRY) triggers a cascade of genes that lead to testis development. If there is no Y chromosome, it triggers a series of pro-female genes that lead to ovarian development.

Dr. Vilain notes that a variation of enzymes or transcription factors can occur at any single step of sex development and alter all the subsequent steps. Depending on the genotype, an individual may experience normal gonadal development, but abnormal development of the genitalia, for example.

He also noted that these genes are critical to determining the differences between men and women in non-gonadal tissues, including differences in gene expression within the brain. One study in the lab of investigator Matt Bramble, Ph.D., investigates if gonadal hormones impact sex differences in the brain by modifying the genome.

This work is a prime example of research informing the care provided to patients and families. Dr. Vilain is also a member of the multidisciplinary clinical team of the PROUD Clinic at Children’s National, a program completely devoted to caring for patients with a wide array of genetic and endocrine issues, including urogenital disorders and variations of sex development.

Sarah Viall

Newborn screening leader selected to advisory committee on heritable disorders in newborns and children

Sarah Viall

Sarah Viall, PPCNP, coordinator for the Newborn Screening Program at the Children’s National Rare Disease Institute (CNRDI), has been invited to serve on the Education and Training Workgroup of the Health Resources & Services Administration’s (HRSA) Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC).

Established under the Public Health Service Act, the ACHDNC focuses on reducing morbidity and mortality in newborns and children who have, or are at risk for, genetic disorders. The Committee currently recommends that all newborn screening programs include a Uniform Screening Panel that monitors for a total of 34 core disorders and another 26 secondary disorders.

In addition to developing recommendations on national newborn screening guidelines, the ACHDNC also advises the U.S. Department of Health and Human Services Secretary on the most appropriate application of newborn screening technologies, tests, policies and standards. The Committee provides technical information that helps develop Heritable Disorders Program policies and priorities that enhance the ability of local and state health agencies to provide screening, healthcare services and counseling for newborns and children affected by genetic disease.

Viall had previously spent a year observing meetings for the ACHDNC Education and Training Workgroup.

“I am thrilled to be an official member that can contribute to the important work of educating communities about newborn screening,” says Viall.

Marshall Summar talks to a colleage in lab

$3M Retrophin gift establishes Rare Disease Network at Children’s National

Marshall Summar talks to a colleage in lab

“This is an exciting first step toward a new era of rare disease care and innovation,” says Marshall Summar, M.D., director of the CNRDI. “We are grateful for this gift from Retrophin that will help us accelerate progress for our patients and families and pursue work that will have a far-reaching impact on both children and adults across the country and around the world thanks to the support of Retrophin.”

Children’s National Health System and Retrophin, Inc. have announced the creation of the Retrophin Rare Disease Network at Children’s National. Retrophin, a biopharmaceutical company specializing in identifying, developing and delivering life-changing therapies to people living with rare diseases, has committed $3 million over the next six years to support the work of the Children’s National Rare Disease Institute (CNRDI). Retrophin’s commitment marks the first corporate gift to CNRDI.

“One of the chief challenges of 21st century pediatric medicine is our continued inability to provide more help to those born with rare genetic diseases,” says Marshall Summar, M.D., director of the CNRDI. “This is an exciting first step toward a new era of rare disease care and innovation. We are grateful for this gift from Retrophin that will help us accelerate progress for our patients and families and pursue work that will have a far-reaching impact on both children and adults across the country and around the world thanks to the support of Retrophin.”

As a dedicated source of funding, the Retrophin Rare Disease Network will advance the CNRDI’s efforts to create a global “hub and spoke” model for disseminating and streamlining patient access to optimal care methods and among national and international peer institutions. The network will enhance the field of rare disease medicine by standardizing care models and establishing world-wide best practices in diagnosis and treatment.

The Retrophin Rare Disease Network will also provide funding for new dedicated positions at the CNRDI and build on the Institute’s existing digital and telemedicine programs, to extend the reach of its researchers and caregivers in areas where there is currently limited care available for children and adults living with rare diseases.

CNRDI is a first-of-its-kind center focused exclusively on advancing the care and treatment of children and adults with rare genetic diseases. The first National Organization for Rare Disorders (NORD) Center of Excellence, it aims to provide a medical home for patients and families seeking the most advanced care and expertise for rare genetic conditions that remain largely unknown to the general medical community.

Children’s National leaders join with Governor Martin O'Malley

Facial analysis technology successfully used to identify Noonan syndrome in diverse populations

facial recognition of noonan syndrome

According to an international study led by the National Human Genome Research Institute (NHGRI), researchers have successfully used facial analysis software, developed by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National, to identify Noonan syndrome in diverse populations.

Noonan syndrome is relatively common, affecting between 1 in 1,000 to 1 in 2,500 children, however few studies have been conducted in non-Europeans. For this study, the researchers evaluated children (average age of eight) with Noonan syndrome from 20 countries. Using the facial analysis software and clinical criteria, the researchers compared 161 white, African, Asian and Latin American children with Noonan syndrome with 161 people of the same age and gender without the disease. Using the software to analyze facial features, they were able to correctly diagnose patients with the disease from each ethnic group with 94 percent or higher accuracy.

“Our algorithm found widely spaced eyes as a significant facial feature in all ethnic groups and also highlighted facial features that are relevant to diagnosing the syndrome in each group,” said

Marius George Linguraru, D.Phil., developer of the facial analysis technology and an investigator in the study from Children’s National.

Linguraru and his team are working to create a simple tool that will enable doctors in clinics without state-of-the-art genetic facilities to take photos of their patients on a smartphone and receive instant results.

Sarah B. Mulkey

Researchers tackle Zika’s unanswered questions

Youssef A. Kousa

Youssef A. Kousa, D.O., Ph.D., M.S., is examining whether interplays between certain genes make some women more vulnerable to symptomatic Zika infections.

A Maryland woman traveled to the Dominican Republic early in her pregnancy, spending three weeks with family. She felt dizzy and tired and, at first, attributed the lethargy to jet lag. Then, she experienced a rash that lasted about four days. She never saw a bite or slapped a mosquito while in the Dominican Republic but, having heard about the Zika virus, asked to be tested.

Her blood tested positive for Zika.

Why was this pregnant woman infected by Zika while others who live year-round in Zika hot zones remain free of the infectious disease? And why was she among the slim minority of Zika-positive people to show symptoms?

Youssef A. Kousa, D.O., Ph.D., M.S., a pediatric resident in the child neurology track at Children’s National Health System, is working on a research study that will examine whether interplays between certain genes make some women more vulnerable to symptomatic Zika infections during pregnancy, leaving  some fetuses at higher risk of developing microcephaly.

Dr. Kousa will present preliminary findings during Research and Education Week 2017 at Children’s National.

At sites in Puerto Rico, Colombia and Washington D.C., Dr. Kousa and his research collaborators are actively recruiting study participants and drawing blood from women whose Zika infections were confirmed in the first or second trimester of pregnancy. The blood is stored in test tubes with purple caps, a visual cue that the tube contains an additive that binds DNA, preventing it from being cut up. Additional research sites are currently being developed.

When the blood arrives at Children’s National, Dr. Kousa will use a centrifuge located in a sample preparation room to spin the samples at high speed for 11 minutes. The sample emerges from the centrifuge in three discrete layers, separated by weight. The rose-colored section that rises to the top is plasma. Plasma contains tell-tale signs of the immune system’s past battles with viruses and will be analyzed by Roberta L. DeBiasi, M.D., M.S., Chief of the Division of Pediatric Infectious Diseases at Children’s National, and Dr. Kousa’s mentor.

A slender line at the middle indicates white blood cells. The dark red layer is heavier red blood cells that sink to the bottom. This bottom half of the test tube, where the DNA resides, is where Dr. Kousa will perform his genetic research.

For years, Dr. Kousa has worked to identify genetic risk factors that influence which fetuses develop cleft lip and palate. In addition to genetic variances that drive disease, he looks at environmental overlays that can trigger genes to respond in ways that cause pediatric disease. When Zika infections raced across the globe, he says it was important to apply the same genetic analyses to the emerging disease. Genes make proteins that carry out instructions, but viral infection disrupts how genes interact, he says. Cells die. Other cells do not fully mature.

While certain poverty-stricken regions of Brazil have recorded the highest spikes in rates of microcephaly, more is at play than socioeconomics, he says. “It didn’t feel like all of the answers lie in the neighborhood. One woman with a Zika-affected child can live just down the street from a child who is more or less severely affected by Zika.”

As a father, Dr. Kousa is particularly concerned about how Zika stunts growth of the fetal brain at a time when it should expand exponentially. “I have three kids. You see them as they achieve milestones over time. It makes you happy and proud as a parent,” he says.

Sarah B. Mulkey

Sarah B. Mulkey, M.D., Ph.D., is studying whether infants exposed to Zika in utero achieve the same developmental milestones as uninfected infants.

While Dr. Kousa concentrates on Zika’s most devastating side effects, his colleague Sarah B. Mulkey, M.D., Ph.D., is exploring more subtle damage Zika can cause to fetuses exposed in utero. In the cohort of Colombian patients that Dr. Mulkey is researching, just 8 percent had abnormal fetal brain magnetic resonance images (MRIs). At first glance, the uncomplicated MRIs appear to be reassuring news for the vast majority of pregnant women.

Dr. Mulkey also will present preliminary findings during Research and Education Week 2017 at Children’s National.

In the fetus, the Zika virus makes a beeline to the developing brain where it replicates with ease and can linger after birth. “We need to be cautious about saying the fetal MRI is ‘normal’ and the infant is going to be ‘normal,’ ” Dr. Mulkey says. “We know with congenital cytomegalovirus that infected infants may not show symptoms at birth yet suffer long-term consequences, such as hearing deficits and vision loss.”

Among Zika-affected pregnancies in Colombia in which late-gestational age fetal MRIs were normal, Dr. Mulkey will use two different evaluation tools at 6 months and 1 year of age to gauge whether the babies accomplish the same milestones as peers. One evaluation tool is a questionnaire that has been validated in Spanish.

At 6 months and 1 year of age, the infants’ motor skills will be assessed, such as their ability to roll over in both directions, sit up, draw their feet toward their waist, stand, take steps independently and purposefully move their hands. Videotapes of the infants performing the motor skills will be scored by Dr. Mulkey and her mentor, Adre du Plessis, M.B.Ch.B., Chief of the Division of Fetal and Transitional Medicine at Children’s National. The Thrasher Research Fund is funding the project, “Neurologic outcomes of apparently normal newborns from Zika virus-positive pregnancies,” as part of its Early Career Award Program.

Both research projects are extensions of a larger multinational study co-led by Drs. du Plessis and DeBiasi that explores the impact of prolonged Zika viremia in pregnant women, fetuses and infants; the feasibility of using fetal MRI to describe the continuum of neurological impacts in Zika-affected pregnancies; and long-term developmental issues experienced by Zika-affected infants.

Teen Girl drawing a heart on an iPad

Illuminating cardiometabolic risk in Down syndrome

Teen Girl drawing a heart on an iPad

A leading researcher at Children’s National says researchers should look closely at the increased risks of obesity and thyroid disease common in patients with Down Syndrome, and determine how these long term comorbidities relate to cardiovascular and metabolic (cardiometabolic) risk, body image, and quality of life.

Over the last several decades, physicians’ improved ability to treat the common comorbidities of Down syndrome, such as congenital heart disease, has dramatically prolonged survival. Today, more than 400,000 people across the country are living with Down syndrome, and life expectancy has increased to 60 years.

New strategies to manage care for patients with Down syndrome must include preventive, evidence-based approaches to address the unique needs of these patients, according to Sheela N. Magge, M.D., M.S.C.E., Director of Research in the Division of Endocrinology and Diabetes at Children’s. She says that these efforts should include looking more closely at the increased risks of obesity and thyroid disease common in this population, and determining how these long term comorbidities relate to cardiovascular and metabolic (cardiometabolic) risk, body image, and quality of life.

An NIH-funded study from Children’s National and the Children’s Hospital of Philadelphia (CHOP), led by Dr. Magge and her colleague from CHOP, Dr. Andrea Kelly, seeks to better understand how the body composition of patients with Down syndrome impacts their likelihood for developing diabetes and obesity-related cardiovascular risks long term.

“We know that individuals with Down syndrome are at increased risk for obesity, but what hasn’t been clear is whether or not they also have the same cardiometabolic risk associated with obesity that we know holds true for other populations,” says Dr. Magge. “In this previously under-studied population, the common assumption based on very limited studies from the 1970’s was that individuals with Down syndrome were protected from the diabetes and cardiovascular risks that can develop in other overweight people. However, more recent epidemiologic studies contradict those early findings.”

The study has enrolled 150 Down syndrome patients and almost 100 controls to date, and the team is currently beginning to analyze the data. Dr. Magge believes that the findings from this study will help to provide new, research-driven evidence to inform the long term clinical management of obesity and cardiometabolic risk in adolescents with Down syndrome.

She concludes, “The goal is for our research to provide the foundation that will advance prevention and treatment strategies for this understudied group, so that individuals with Down syndrome not only have a longer life expectancy, but also a healthier and better quality of life.”

Sarah B. Mulkey

Puzzling symptoms lead to collaboration

Sarah B. Mulkey, explaining the research

Sarah B. Mulkey, M.D., Ph.D., is lead author of a study that describes a brand-new syndrome that stems from mutations to KCNQ2, a genetic discovery that began with one patient’s unusual symptoms.

Unraveling one of the greatest mysteries of Sarah B. Mulkey’s research career started with a single child.

At the time, Mulkey, M.D., Ph.D., a fetal-neonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National Health System, was working at the University of Arkansas for Medical Sciences. Rounding one morning at the neonatal intensive care unit (NICU), she met a new patient: A newborn girl with an unusual set of symptoms. The baby was difficult to wake and rarely opened her eyes. Results from her electroencephalogram (EEG), a test of brain waves, showed a pattern typical of a severe brain disorder. She had an extreme startle response, jumping and twitching any time she was disturbed or touched, that was not related to seizures. She also had trouble breathing and required respiratory support.

Dr. Mulkey did not know what to make of her new patient: She was unlike any baby she had ever cared for before. “She didn’t fit anything I knew,” Dr. Mulkey remembers, “so I had to get to the bottom of what made this one child so different.”

Suspecting that her young patient’s symptoms stemmed from a genetic abnormality, Dr. Mulkey ran a targeted gene panel, a blood test that looks for known genetic mutations that might cause seizures or abnormal movements. The test had a hit: One of the baby’s genes, called KCNQ2, had a glitch. But the finding deepened the mystery even further. Other babies with a mutation in this specific gene have a distinctly different set of symptoms, including characteristic seizures that many patients eventually outgrow.

Dr. Mulkey knew that she needed to dig deeper, but she also knew that she could not do it alone. So, she reached out first to Boston Children’s Hospital Neurologist Philip Pearl, M.D., an expert on rare neurometabolic diseases, who in turn put her in touch with Maria Roberto Cilio, M.D., Ph.D., of the University of California, San Francisco and Edward Cooper, M.D., Ph.D., of Baylor College of Medicine. Drs. Cilio, Cooper and Pearl study KCNQ2 gene variants, which are responsible for causing seizures in newborns.

Typically, mutations in this gene cause a “loss of function,” causing the potassium channel to remain too closed to do its essential job properly. But the exact mutation that affected KCNQ2 in Dr. Mulkey’s patient was distinct from others reported in the literature. It must be doing something different, the doctors reasoned.

Indeed, a research colleague of Drs. Cooper, Cilio and Pearl in Italy — Maurizio Taglialatela, M.D., Ph.D., of the University of Naples Federico II and the University of Molise — had recently discovered in cell-based work that this particular mutation appeared to cause a “gain of function,” leaving the potassium channel in the brain too open.

Wondering whether other patients with this same type of mutation had the same unusual constellation of symptoms as hers, Dr. Mulkey and colleagues took advantage of a database that Dr. Cooper had started years earlier in which doctors who cared for patients with KCNQ2 mutations could record information about symptoms, lab tests and other clinical findings. They selected only those patients with the rare genetic mutation shared by her patient and a second rare KCNQ2 mutation also found to cause gain of function — a total of 10 patients out of the hundreds entered into the database. The researchers began contacting the doctors who had cared for these patients and, in some cases, the patients’ parents. They were scattered across the world, including Europe, Australia and the Middle East.

Dr. Mulkey and colleagues sent the doctors and families surveys, asking whether these patients had similar symptoms to her patient when they were newborns: What were their EEG results? How was their respiratory function? Did they have the same unusual startle response?

She is lead author of the study, published online Jan. 31, 2017 in Epilepsia, that revealed a brand-new syndrome that stems from specific mutations to KCNQ2. Unlike the vast majority of others with mutations in this gene, Dr. Mulkey and her international collaborators say, these gain-of-function mutations cause a distinctly different set of problems for patients.

Dr. Mulkey notes that with a growing focus on precision medicine, scientists and doctors are becoming increasingly aware that knowing about the specific mutation matters as much as identifying the defective gene. With the ability to test for more and more mutations, she says, researchers likely will discover more cases like this one: Symptoms that differ from those that usually strike when a gene is mutated because the particular mutation differs from the norm.

Such cases offer important opportunities for researchers to come together to share their collective expertise, she adds. “With such a rare diagnosis,” Dr. Mulkey says, “it’s important for physicians to reach out to others with knowledge in these areas around the world. We can learn much more collectively than by ourselves.”

Lisa M. Guay-Woodford, M.D

Lisa Guay-Woodford: minimizing kidney disease effects

Lisa M. Guay-Woodford, M.D

Lisa M. Guay-Woodford, M.D., is internationally recognized for her examination of the mechanisms that make certain inherited renal disorders particularly lethal, a research focus inspired by her patients.

The artist chose tempera paint for her oeuvre. The flower’s petals are the color of Snow White’s buddy, the Bluebird of Happiness. Each petal is accentuated in stop light red, and the blossom’s leaves stretch up toward the sun. With its bold strokes and exuberant colors, the painting exudes life itself.

It’s the first thing Lisa M. Guay-Woodford, M.D., sees when she enters her office. It’s the last thing she sees as she leaves.

Dr. Guay-Woodford, a pediatric nephrologist, is internationally recognized for her research into the mechanisms that make certain inherited renal disorders, such as autosomal recessive polycystic kidney disease (ARPKD), particularly lethal. She also studies disparate health disorders that have a common link: Disruption to the cilia, slim hair-like structures that protrude from almost every cell in the human body and that play pivotal roles in human genetic disease.

Sarah, the artist who painted the bright blue flower more than 20 years ago when she was 8, was one of Dr. Guay-Woodford’s patients. And she’s part of the reason why Dr. Guay-Woodford has spent much of her career focused on the broader domain of disorders tied to just a single defective gene, such as ARPKD.

“It dates back to when I was a house officer and took care of kids with this disorder,” Dr. Guay-Woodford says. “Maybe 30 percent die in the newborn period. Others survive, but they have a whole range of complications.”

Two of her favorite patients died from ARPKD-related reasons in the same year. One died from uncontrolled high blood pressure. The other, Sarah, died from complications from a combined kidney and liver transplant.

“The picture she drew hangs in my office,” she says. “She was a wonderful kid who was really full of life, and what she chose really mirrored who she was as a person. We put up lots of those sorts of those things in my office. It’s a daily reminder of why we do the things we do and the end goal.”

ARPKD is characterized by the growth of cysts in the liver, the kidney – which can lead to kidney failure – and complications within other structures, such as blood vessels in the heart and brain, according to the National Institutes of Health. About 1 in 20,000 live births is complicated by the genetic disorder. The age at which symptoms arise varies.

“Given the way it plays out, starting in utero, this is not a disease we are likely to cure,” she says. “But there are children who have very minimal complications. The near-term goal is to use targeted therapies to convert the children destined to have a more severe disease course to one that is less complicated so that no child suffers the full effects of the disease.”

That’s why it is essential to attain detailed knowledge about the defective gene responsible for ARPKD. To that end, Dr. Guay-Woodford participated in an international collaboration – one of three separate groups that 14 years ago identified PKHD1 as the defective gene that underlies ARPKD.

“The progress has been slow, partly because the gene and its protein products are very complex,” she says. “The good news is the gene has been identified. The daunting news is the identification did not leap us forward. It is just sort of an important step in what is going to be a fits-and-starts kind of journey.”

The field is trying to emulate the clinical successes that have occurred for patients with cystic fibrosis, which now can be treated by a drug that targets the defective gene, attacking disease at a fundamental level. Patient outcomes also have improved due to codifying care.

When she was a resident in the 1980s, children with cystic fibrosis died in their teens. “Now, they’re living well into their 40s because of careful efforts by really astute clinicians to deliver a standardized approach to care, an approach now enhanced by a terrific new drug. We measure quality care in terms of patient outcomes. That has allowed us to really understand how to effectively use antibiotics, physical therapy and how to think about nutrition – which makes a hugely important contribution that previously had been underappreciated.”

Standardizing clinical approaches dramatically improved and extended patients’ lives. “For renal cystic disease, we are beginning to do that better and better,” she adds.

There’s no targeted medicine yet for ARPKD. But thanks to an international conference that Dr. Guay-Woodford convened in Washington in 2013, such consensus expert recommendations have been published to guide diagnosis, surveillance and management of pediatric patients with ARPKD.

“There is an awful lot we can do in the way we systematically look at the clinical disease in these patients and improve our management. And, if you can overlay on top of that specific insights about why one person goes one way in disease progression versus another way, I think we can boost the baseline by developing good standards of care,” she says.

“Science does march on. There are a number of related research studies that are expanding our understanding of ARPKD. Within the next decade, we probably will be able to capitalize on not just the work in ARPKD but work in related diseases to learn the entry points for targeting therapies. That way, we can build a portfolio of markers of disease progression and test how effective these potential therapies are in slowing the course of the disease.”

Cleft lip and palate: caught in the web of genetic interactions

Children’s National research scientists are working to unravel the complicated web of genetic interactions that lead children to develop cleft lip and palate.

On June 26, 2000, scientists around the world hailed the first draft of the human genetic code as a scientific milestone that eventually would revolutionize the practice of medicine. By knowing the approximately 20,000 protein-coding genes for humans, many speculated that researchers and doctors eventually might elucidate the unique factors that influence thousands of diseases—and, someday, make it easier to find custom ways to treat these conditions.

“It is humbling for me and awe inspiring to realize that we have caught the first glimpse of our own instruction book, previously known only to God,” said Francis S. Collins, M.D., Ph.D., who directed the international effort to sequence the human genome and who now directs the National Institutes of Health.

Nearly two decades later, actually using this wealth of information has proven exceedingly more complicated than many envisioned. While some genetic diseases like Huntington’s disease or sickle cell anemia follow a simple pattern in which variations in a single gene lead to deleterious effects, the vast majority of other genetic health problems result from the interaction of multiple genes, from a handful to hundreds.

One condition that has proven especially tricky to understand on the genetic level is cleft lip and palate (CLP), says Youssef A. Kousa, D.O., Ph.D., a pediatric neurology resident at Children’s National Health System who has made human development a central focus of his research program. CLP, which affects about 1 in 1,000 babies born worldwide, can be devastating, Kousa explains. At some point between 6 and 12 weeks gestation, the palate and lip fail to close in some fetuses. Those children are born with a fissure that can significantly impair eating and speaking and that can complicate social interactions.

While researchers have linked some genes to CLP, Kousa says it has become increasingly clear that these genes do not exert their influence in isolation. In a review paper published recently in Developmental Dynamics, he and Brian C. Schutte, Ph.D., of Michigan State University, detail the story of three of those genes. The trio plays a role in CLP but also is implicated in another devastating congenital problem, neural tube defects.

One of these genes is IRF6, which scientists tagged as the gene responsible for inherited forms of CLP called van der Woude syndrome and popliteal pterygium syndrome more than a decade ago. In the interim, research has shown IRF6 also appears to be important in orofacial clefting that occurs independently of these syndromes. Estimates suggest that mutations in IRF6 increase the risk for CLP by 12 percent to 18 percent.

That means at least 80 percent of the risk for clefting is caused by different genes. Kousa and Schutte write that one of these is GRHL3, which also can cause van der Woude syndrome if it is mutated. GRHL3 is regulated by IRF6, Kousa explains. So, if IRF6 does not work properly, neither does GRHL3.

But what regulates IRF6? Upstream of this important gene is another called TFAP2A. The healthy operation of TFAP2A is key for IRF6 and orofacial clefting. Complicating the scenario further, several studies also have shown that TFAP2A is essential for normal development of the palate and neural tube, the embryo’s precursor to the central nervous system that eventually develops into the brain and spinal cord.

To shed light on the interplay of the full array of genes involved CLP, Kousa and colleagues recently published a paper in Birth Defects Research in which they use computer programs to analyze datasets on all genes identified thus far that are involved in orofacial and neural tube development and which molecules these genes produce and target. Their analyses showed that many of these genes are linked in associated pathways that influence vast realms of development, risk of cancer and folate metabolism. (Women who take folic acid supplements before getting pregnant and during pregnancy can reduce birth defect risks.)

By better understanding how these genes are connected into networks, Kousa says, researchers may be able to reduce the risk of both CLP and neural tube defects with a single intervention. However, like the study of genetic diseases itself, finding the right intervention might not be so simple. A drug or supplement that can alleviate one condition might exacerbate others, based on the complicated web of genetic interactions, he says.

“That’s why work from our lab and others is so important,” Kousa says. “It adds layers and layers of knowledge that, eventually, we’ll be able to put together to help prevent these devastating problems.”

Zhe Han, PhD

Key to genetic influence of APOL1 on chronic kidney disease

Zhe Han

Drosophila melanogaster nephrocytes share structural and functional similarities with human renal cells, making the fruit fly an ideal pre-clinical model for studying how the APOL1 gene contributes to renal disease in humans.

Using the Drosophila melanogaster pre-clinical model, a Children’s National Health System research team identified a key mechanism by which the APOL1 gene contributes to chronic kidney disease in people of African descent. The model exploits the structural and functional similarities between the fruit fly’s nephrocytes and renal cells in humans to give scientists an unprecedented ability to study gene-to-cell interactions, identify other proteins that interact with APOL1 in renal disease, and target novel therapies, according to a paper published November 18 in the Journal of the American Society of Nephrology.

“This is one of the hottest research topics in the kidney field. We are the first group to generate this result in fruit flies,” says Zhe Han, Ph.D., a senior Drosophila specialist and associate professor in the Center for Cancer & Immunology Research at Children’s National. Han, senior author of the paper, presented the study results this month during Kidney Week 2016, the American Society of Nephrology’s annual gathering in Chicago that was expected to draw more than 13,000 kidney professionals from around the world.

The advantages of Drosophila for biomedical research include its rapid generation time and an unparalleled wealth of sophisticated genetic tools to probe deeply into fundamental biological processes underlying human diseases. People of African descent frequently inherit a mutant version of the APOL1 gene that affords protection from African sleeping sickness, but is associated with a 17- to 30-fold greater chance of developing certain types of kidney disease. That risk is even higher for individuals infected with the human immunodeficiency virus (HIV). Drosophila renal cells, called nephrocytes, accurately mimic pathological features of human kidney cells during APOL1-associated renal disease.

“Nephrocytes share striking structural and functional similarities with mammalian podocytes and renal proximal tubule cells, and therefore provide us a simple model system for kidney diseases,” says Han, who has studied the fruit fly for 20 years and established the fly nephrocyte as a glomerular kidney disease model in 2013 with two research papers in the Journal of the American Society of Nephrology.

In this most recent study, Han’s team cloned a mutated APOL1 gene from podocyte cells cultured from a patient with HIV-associated nephropathy. They created transgenic flies making human APOL1 in nephrocytes and observed that initially the transgene caused increased cellular functional activity. As flies aged, however, APOL1 led to reduced cellular function, increased cell size, abnormal vesicle acidification, and accelerated cell death.

“The main functions of nephrocytes are to filter proteins and remove toxins from the fly’s blood, to reabsorb protein components, and to sequester harmful toxins. It was surprising to see that these cells first became more active and temporarily functioned at higher levels,” says Han. “The cells got bigger and stronger but, ultimately, could not sustain that enhancement. After swelling to almost twice their normal size, the cells died. Hypertrophy is the way that the human heart responds to stress overload. We think kidney cells may use the same coping mechanism.”

The Children’s research team is a multidisciplinary group with members from the Center for Cancer & Immunology Research, the Center for Genetic Medicine Research, and the Division of Nephrology. The team also characterized fly phenotypes associated with APOL1 expression that will facilitate the design and execution of powerful Drosophila genetic screening approaches to identify proteins that interact with APOL1 and contribute to disease mechanisms. Such proteins represent potential therapeutic targets. Currently, transplantation is the only option for patients with kidney disease linked to APOL1.

“This is only the beginning,” Han says. “Now, we have an ideal pre-clinical model. We plan to start testing off-the-shelf therapeutic compounds, for example different kinase inhibitors, to determine whether they block any of the steps leading to renal cell disease.”

Doctors working together to find treatments for autoimmune encephalitis

Children’s and Regeneron partner in exome sequencing study

Children’s National, in partnership with the Regeneron Genetics Center (RGC, a subsidiary of Regeneron Pharmaceuticals, Inc.), has announced the launch of a major three-year research study that will examine the links between undiagnosed disease and an individual’s genetic profile.

The program, directed by Children’s National Geneticist Carlos Ferreira Lopez, M.D., and coordinated by Genetic Counselor Lindsay Kehoe, hopes to include as many as 3,000 patients in its initial year and even greater numbers in the following two years.

During the course of the study, RGC will conduct whole exome sequencing (WES) to examine the entire protein-coding DNA in a patient’s genome. Children’s National geneticists will analyze and screen for certain findings that are known to be potentially causative or diagnostic of disease. Children’s National scientists and providers will confirm preliminary research findings in a lab certified for Clinical Laboratory Improvement Amendments (CLIA), per federal standards for clinical testing, and refer any confirmatory CLIA-certified cases to appropriate clinicians at Children’s National for further care.

According to Marshall Summar, M.D., Chief of Genetics and Metabolism at Children’s National, the WES study could finally provide patients and their families with the medical answers they have been looking for, allowing for treatment appropriate to their specific genetic condition.

Because pediatric diseases can often elude diagnosis, they can pose a number of detrimental effects to patients and their families, including treatment delays, multiple time- and cost-intensive tests, and stress from lingering uncertainty regarding the illness. With this genomic data, Regeneron will be able to utilize findings to continue its efforts to improve drug development.

Since its inception in 2014, the RGC has strategically partnered with leading medical institutions to utilize human genetics data to speed the development and discovery of new and improved therapies for patients in need.

Why subtle cellular changes can result in dramatically different genetic disorders

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What’s Known
One single gene, lamin A/C, is to blame for a multitude of genetic disorders, such as premature aging and problems with nerves, the heart, and muscles. Uncertainties linger in the scientific and medical community about why subtle changes of this gene cause such dramatically different disorders, such as Emery-Dreifuss muscular dystrophy, a condition that can lead to progressive muscle weakness in childhood and heart problems by adulthood.

What’s New
The nuclear envelope is where attached regions are pulled from genetic circulation never to be used again. The process of attachment signals which parts of the genome the cell no longer considers useful. Discarding superfluous DNA keeps the cell focused on what matters more: Its future role. Proper cell differentiation hinges on “the coordinated execution of three key cellular programs,” the study authors write. Pluriopotency programs, which give primitive cells the remarkable ability to generate any cell type in the body, are inactivated. Exit from the cell cycle occurs, and cells stop dividing. Myogenesis is induced, ushering in formation of muscle tissue. Mutations in lamin A/C can disrupt this careful choreography with the cumulative effect of slowing exit from cell cycle, slowing exit from pluripotency programs, and poorly coordinating induction of terminal differentiation programs.

Questions for Future Research
Q: What are the regions of human genome that become attached to the nuclear envelope during the development of tissues other than muscle (such as fat, nerve, and heart)?
Q: Can medicines that influence epigenetic pathways help to reverse the inappropriate DNA-lamin associations in Emery-Dreifuss muscular dystrophy?
Q: Can the new knowledge of DNA-lamin associations during muscle cell differentiation help to inform stem cell therapies?

Source: “Laminopathies Disrupt Epigenomic Developmental Programs and Cell Fate.” J. Perovanovic, S. Dell’Orso, V.F. Gnochi, J. K. Jaiswal, V. Sartorelli, C. Vigouroux, K. Mamchaoui, V. Mouly, G. Bonne, and E. P. Hoffman. Science Translational Medicine. April 20, 2016.

Clinicopathology of diffuse intrinsic pontine glioma and its redefined genomic and epigenomic landscape

Dr. Nazarian's lab

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What’s Known
Fewer than 150 U.S. children per year are diagnosed with diffuse intrinsic pontine glioma (DIPG), one of the most lethal pediatric central nervous system cancers. Despite an increasing number of experimental therapies tested via clinical trials, more than 95 percent of these children die within two years of diagnosis. Molecular studies have yielded additional insight about DIPG, including that mutations in histone-encoding genes are associated with 70 percent of cases. Understanding mutations that drive tumors and the genomic landscape can help to guide development of targeted therapies.

What’s New: Frequently found genetic alterations prevalent in DIPGs

dipg-gene-mutations-and-biological-consequences

Source: “Clinicopathology of Diffuse Intrinsic Pontine Glioma and Its Redefined Genomic and Epigenomic Landscape.” E. Panditharatna, K. Yaeger, L.B. Kilburn, R.J. Packer, and J. Nazarian. Published by Cancer Genetics on May 1, 2015.