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Children’s National Hospital joins the Mendelian Genomics Research Consortium, receiving $12.8 million

July 15, 2021

Dr. Eric Vilain accompanied by a fellow researcher at the new Research & Innovation Campus.

Children’s National Hospital announces a $12.8 million award from the National Institutes of Health’s National Human Genome Research Institute (NHGRI) to establish the only Pediatric Mendelian Genomics Research Center (PMGRC) as part of a new Mendelian Genomics Research Consortium. Researchers at Children’s National and Invitae — a leading medical genetics company — will identify novel causes of rare inherited diseases, investigate the mechanisms of undiagnosed conditions, enhance data sharing, and generally interrogate Mendelian phenotypes, which are conditions that run in families.

“Our overall approach provides an efficient and direct path for pediatric patients affected with undiagnosed inherited conditions through a combination of innovative approaches, allowing individuals, families and health care providers to improve the management of the disease,” says Eric Vilain, M.D., Ph.D., director of the Center for Genetic Medicine Research at Children’s National.

To accelerate gene discovery for Mendelian phenotypes and the clinical implementation of diagnosis, the consortium will leverage the broad pediatric clinical and research expertise of the Children’s National Research Institute and laboratories in partnership with Invitae. The Molecular Diagnostics Laboratory at Children’s National will provide genetic testing for patients in the Washington, D.C., metropolitan area. Invitae will provide genetic testing for patients from elsewhere in the U.S., giving the project a national reach and allowing researchers to leverage more robust data. Integrative analyses will be performed jointly with scientists at Children’s National and Invitae.

“Some patients have genetic test results that are ‘negative,’ meaning the results do not explain their condition. When a patient receives a negative result, it is challenging for parents and doctors to know what to do next,” says Meghan Delaney, D.O., M.P.H., chief of the Division of Pathology and Laboratory Medicine and Molecular Diagnostics Laboratory at Children’s National. “The project will provide an avenue to possibly find an explanation of their child’s condition. Besides filling an important clinical gap, the results will add new knowledge for future patients and the scientific community.”

“Too often parents of children suffering from a rare condition find themselves in a protracted diagnostic odyssey when early intervention could mean better overall outcomes,” says Robert Nussbaum, M.D., chief medical officer of Invitae. “We are proud to partner with Children’s National Research Institute on this important effort to identify the genetic cause of these rare conditions earlier and improve the chances that children with such conditions can receive the appropriate treatments and live healthier lives.”

Deciphering Mendelian conditions will help diagnose more of the estimated 7,000 rare inherited diseases and predict the tremendous variability of clinical presentations in both rare and common conditions caused by the same gene.

There is also a need to establish a new standard of care to bridge the gap in the use of genomic information from diagnosis to improved outcomes. The consortium will establish best practices for obtaining a genetic diagnosis, offering an explanation for the condition to affected patients, and is likely to provide additional explanations for basic biological mechanisms, increasing the knowledge of physiopathology and possibly leading to better condition management.

The PMGRC will enroll an average of 2,600 participants per year with suspected Mendelian phenotypes and previously non-diagnostic tests and their family members. The integration of multiple genomic technologies, including short and long read genome sequencing, optical genome mapping and RNA-sequencing, will enable these discoveries. To disambiguate uncertain variants and candidate genes, the PMGRC will use whole transcriptome analysis, RNA-sequencing, CRE-sequencing and functional modeling.

Since many Mendelian conditions first appear prenatally or during infancy, Children’s National will have a unique bed-to-bench-to-bed symbiosis. Patients eligible for the study will come from across the multiple specialty divisions of Children’s National, including the Children’s National Rare Disease Institute, and nationally through the partnership with Invitae. From there, experts from the Children’s National Center for Genetic Medicine Research will enroll patients and integrate the initial clinical test results with broad-based genomic interrogation, leading to new diagnoses and novel discoveries. Finally, the results will be verified and returned to clinicians, which will help inform targeted therapies.

Typically, the patients eligible for this study jump from specialist to specialist without an answer, have a condition that appears in other family members or they have symptoms involving more than one affected organ, which suggests a complex developmental condition. The PMGRC at Children’s National will help find answers to the causes of many puzzling pediatric conditions, providing faster clinical diagnoses and opening up pathways to potentially better treatments.

Dr. Vilain’s work will be based at the Children’s National Research & Innovation Campus on the grounds of the former Walter Reed Army Medical Center in Washington, D.C. The campus is also home to the Children’s National Rare Disease institute — one of the largest clinical genetics program in the United State that provides care to more than 8,500 rare disease patients.

Commercialization of novel facial analysis technology can improve diagnosis of rare disorders in pediatric patients

July 14, 2021

Children’s National Hospital has entered into a licensing agreement with MGeneRx Inc. for its patented pediatric medical device technology using objective digital biometric analysis software for the early and non-invasive screening of dysmorphic genetic diseases such as Noonan syndrome.

Children’s National Hospital has entered into a licensing agreement with life sciences technology company MGeneRx Inc. for its patented pediatric medical device technology using objective digital biometric analysis software for the early and non-invasive screening of dysmorphic genetic diseases. The technology, developed by a multidisciplinary Children’s National team led by Marius George Linguraru, D.Phil, M.A., M.Sc., of the Sheikh Zayed Institute for Pediatric Surgical Innovation and Marshall Summar, M.D., director of the Children’s National Rare Disease Institute (CNRDI), can provide a more advanced diagnostic tool for regions of the world with limited access to geneticists or genetic testing.

The application utilizes artificial intelligence (AI) and machine learning to analyze biometric data and identify facial markers that are indicative of genetic disorders. Physicians can capture biometric data points of a child’s face in real time within the platform, where it scans facial biometric features to determine the potential presence of a genetic disease, which can often be life-threatening without early intervention. Research studies conducted in conjunction with the National Human Genome Research Institute at the National Institutes of Health further enhanced the development of the application in recent years, showing the potential to detect, with a 90 percent accuracy, early diagnosis of 128 genetic diseases across pediatric subjects in 28 countries. These diseases include DiGeorge syndrome (22q11.2 deletion syndrome), Down syndrome, Noonan syndrome and Williams-Beuren syndrome.

“We are delighted to enter into this licensing agreement through Innovation Ventures, the commercialization arm of Children’s National Hospital, which seeks to move inventions and discoveries from Children’s National to the marketplace to benefit the health and well-being of children. Our mission is to add the ‘D’ in development to the ‘R’ in research to accelerate the commercialization of our intellectual property,” says Kolaleh Eskandanian, Ph.D., M.B.A., P.M.P., vice president and chief innovation officer at Children’s National and managing director of Innovation Ventures. “It is through partnerships with startups and the industry that we can achieve this goal and thus we highly value this new partnership with MGeneRx Inc. The acceleration and commercialization of this objective digital biometric analysis technology will not only help diagnose rare genetic disorders – it will also allow for earlier interventions that improve the quality of life for the children living with these conditions.”

Eskandanian adds that the social impact of this technology is especially profound in lower income nations around the world, where there is a high prevalence of rare genetic conditions but a severe lack in the specialty care required to diagnose and treat them. Additional data collected through the expanded use of the technology will help to further develop the application and expand its capabilities to identify and diagnose additional rare genetic conditions.

The licensing agreement was arranged by the Children’s National Office of Innovation Ventures, which is focused on the commercialization of impactful new pediatric medical device technologies and therapies to advance children’s health care. Created to catalyze the ongoing translational research of the Children’s National Research Institute (CNRI) as well as inventions by hospital’s clinicians, Innovation Ventures focuses on four core pillars to advance pediatric medical technologies including a Biodesign program, partnerships and alliances to augment internal capacity, seed funding to de-risk technologies and validate market and clinical relevance, and back-office operations to manage intellectual property and licensing activities. Since 2017, Children’s National intellectual property has served as the basis for over 15 licensing or option agreements with commercial partners.

Providing access to an array of experts and resources for pediatric innovators is one of the aims of the Children’s National Research & Innovation Campus, a first-of-its-kind focused on pediatric health care innovation, with the first phase currently open on the former Walter Reed Army Medical Center campus in Washington, D.C. With its proximity to federal research institutions and agencies, universities, academic research centers, as well as on-site incubator Johnson and Johnson Innovation – JLABS, the campus provides a rich ecosystem of public and private partners, which will help bolster pediatric innovation and commercialization.

How a baby with classic galactosemia was nearly missed: When the test succeeds but system fails

April 28, 2020

Run at the state-level, mandatory newborn screening (NBS) programs detect a host of hereditary disorders so that infants can be treated before further damage, or even death, occurs.

Newborn screening (NBS) programs are critical to public health. Run at the state-level, mandatory NBS programs detect a host of hereditary disorders so that infants can be treated before further damage, or even death, occurs.

While much attention is paid to testing technology, programs must still meet basic minimum requirements to reliably identify and treat all affected individuals including minimum reporting requirements, case surveillance and a dedicated short-term follow-up program. In newborn screening, success is systematic.

A new report “How a baby with classic galactosemia was nearly missed: When the test succeeds but system fails,” published in the American Journal of Medical Genetics, takes a look at an individual case that almost slipped through the cracks of a local NBS program.

One disorder detected by NBS is classic galactosemia (CG), which arises from a deficiency in the galactose-1-phosphate uridyltransferase (GALT) enzyme, leaving infants unable to metabolize galactose-1-phosophate, a monosaccharide abundantly present in milk. CG can result in fatal liver failure, sepsis and coagulopathy if the affected infant is not switched to soy-based formula within the first week of life.

CG can be detected through a combination of enzyme assay, DNA analysis and galactose quantification. However, NBS programs differ in testing protocols for CG by state, and not all NBS programs conduct all of these tests. This is of particular relevance to the Washington, D.C., metropolitan area, a regional nexus where crossing state and district lines for medical care is common.

The report describes how a D.C.-born infant was screened for CG through all three tests. While his galactose levels were normal, his GALT was low and DNA testing revealed homozygosity for a CG mutation known as K285N. In tandem, the latter two indicators constitute a true positive result for CG, and necessitate the proper issuance of referrals, precautions and follow-up, which failed to occur in this case.

The infant breastfed and displayed notable lethargy, and parents were directed to a local emergency department in a neighboring state which does not screen for CG with DNA testing.

The providers there were unfamiliar with the DNA results, and after new labs came back normal, the NBS results were deemed as “likely falsely positive” for CG. Fortunately, a provider at the community hospital forwarded the NBS results to the Children’s National Rare Disease Institute (CNRDI). Upon review, CNRDI metabolic specialists immediately sought to rectify the situation by reaching out to the family with proper instructions and arranging a clinical evaluation, which occurred 10 days after birth.

While this case had a fortunate ending, the report highlights the potential deficiencies in NBS programs, which have historically been among America’s most successful public health initiatives. The proper and timely functioning of NBS systems is contingent upon the functioning of its constituent parts, including testing, diagnosis, follow-up, management and stakeholder education.

While test results were accurate in this case, systemic shortcomings left a patient in danger. As the authors state, “Programs must keep in mind that the true success of newborn screening extends beyond just the test itself…to improve safety and care outcomes we must focus on the system.”

A clinical report by a team of authors, mainly comprised of Children’s National clinicians, was published earlier this month in the American Journal of Medical Genetics. Authors include Sarah Viall, PPCNP, MSN, a pediatric nurse practitioner in the Rare Disease Institute; Nicholas Ah Mew, M.D., director of the Inherited Metabolic Disorders Program; and Beth A. Tarini, M.D., M.S., associate director of the Center for Translational Research.