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Dr. Eric Vilain and researcher in a lab

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

Dr. Eric Vilain and researcher in a lab

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.

The Children's National Research & Innovation Campus

Children’s National Research & Innovation Campus welcomes Rare Disease Institute as first occupant

The Children's National Research & Innovation Campus

The Rare Disease Institute, which includes the largest clinical group of pediatric geneticists in the nation, focuses on developing the clinical care field of the more than 8,000 rare diseases currently recognized and advancing the best possible treatments for children with these diseases.

The Children’s National Research & Innovation Campus (RIC), the first-of-its-kind pediatric research and innovation hub located in Washington, D.C., now has its first occupant – the Rare Disease Institute (RDI).

The institute, which includes the largest clinical group of pediatric geneticists in the nation, focuses on developing the clinical care field of the more than 8,000 rare diseases currently recognized and advancing the best possible treatments for children with these diseases.

With the advent of advanced DNA sequencing, databanks, informatics, new technology, pediatric consortiums and global partnerships, clinical researchers have never been in a better position to diagnose and treat rare diseases. As this field of medicine continues to rapidly evolve, the benefits provided to patients, families, clinicians and researchers through its new home at the RIC will further accelerate the trajectory of rare disease from an academic specialty into a mainstream medical field.

Marshall Summar, M.D., director of the RDI and chief of the Division of Genetics and Metabolism at Children’s National, is well-known for pioneering work in caring for children diagnosed with rare diseases. He developed and launched the world’s first RDI at Children’s National in 2017, and it became the first Clinical Center of Excellence designated by the National Organization for Rare Diseases (NORD). Dr. Summar discusses how this move will positively impact treatment, services and discovery on a national level.

Q: What are the patient benefits of the move to the RIC?

A: Patients with genetic conditions spend a lot of time visiting the hospital. By creating an easy access environment that is designed around their needs, we can provide world-class care to the families we work with. We designed extensive telemedicine capacity into the clinic so we can continue to expand our digital reach to wider areas. The parking facility is also a huge plus for our families with mobility impairments. The garage is only steps away from the clinic entrance. The architectural team worked closely with the clinical team to create a patient-centric facility for a safe and positive experience.

Q: What are the research benefits of being on the RIC?

A: One of our core goals at the RIC was to create research “neighborhoods.” A focus of the first phase of the RIC occupancy is genetics and the RDI is the clinical manifestation of that focus. Having the clinical service that sees patients with genetic disease, sharing space and campus with the Center for Genetic Medicine Research team and the molecular genetics laboratory creates that thematic neighborhood. Some of the best basic science ideas and projects come from the clinical world. Close interaction between the clinicians and the scientists will enhance those “spark” encounters. In addition, the physicians in the RDI who do bench research are also part of the genetic medicine program which furthers these interactions.

Marshall Summar

Marshall Summar, M.D., director of the RDI and chief of the Division of Genetics and Metabolism at Children’s National.

Q: What would you say has been the most significant change to your field in the past decade?

A: The ability to access next-generation genetic sequencing for more and more of our patients. The percentage of patients who can get a meaningful diagnosis with these technologies increases every year. With these techniques, we are finding new links between genes and disease at the rate of 5-10 per week.

Q: What excites you most about the future of medical genetics and rare diseases?

A: Two things are really exciting to me. The first is the ability to diagnose more patients than at any time in history. The second is the rate at which new genetic/rare disease therapies are being developed (around 50% of the FDA new drug approvals per year).

As the largest clinical program in North America and with our new location on this dedicated research and innovation campus in Washington, D.C., Children’s National and the RDI are uniquely poised to dramatically change the field of rare disease medicine. Our clinical models have started spreading to other centers across the country and will help shape the field for years to come. We are evolving rare disease into a true mainstream medical field, and the ability to make this type of change to a field is very unique to Children’s National.

Learn more about the Children’s National Research & Innovation Campus.

Test tube that says IGF-1 test

A new algorithm: Using genomics and EHR to detect severe growth disorders

Test tube that says IGF-1 test

Andrew Dauber, M.D., MMSc., a pediatric endocrinologist and the chief of endocrinology at Children’s National, guided research presented at ENDO 2019, the Endocrine Society’s annual meeting, enabling clinicians and researchers to understand the genetic underpinnings of certain pediatric growth disorders, while using electronic health record (EHR) algorithms to screen for presenting symptoms in the exam room. In some cases, this prompts further genetic testing and shortens the diagnostic odyssey for pediatric growth disorders – such as Turner syndrome.

Here is a summary of the research findings, delivered as two oral abstracts and a poster session.

ABSTRACT 1: Presented on Saturday, March 23, at 12:30 p.m. CST

Healthy childhood growth cohort provides insight into PAPPA2 and IGF-1 relationship, revealing a new level of complexity to the biology of growth with implications for the study and treatment of severe growth disorders

Program: Growth, puberty, and insulin action and resistance

Session OR07-5: A Cross-Sectional Study of IGF-I Bioavailability through Childhood: Associations with PAPP-A2 and Anthropometric Data

Background: Insulin-like growth factor 1 (IGF-1) is a hormone essential for human growth and is often bound to IGFBP-3, an IGF binding protein. Pregnancy Associated Plasma Protein-A2 (PAPP-A2) cleaves intact IGFBP-3, freeing IGF-1 to support normal growth functions. This is the first study, led by Dr. Andrew Dauber with collaborators from Cincinnati Children’s Hospital Medical Center, to track PAPP-A2 and intact IGFBP-3 concentrations throughout childhood. The research team studied 838 healthy children, ages 3-18, in the Cincinnati Genomic Control Cohort, to better understand patterns of growth and development by examining the relationship between PAPPA2 and IGF-1 bioavailability.

Study results: Free IGF-1 increased with age. PAPP-A2, a positive modulator of IGF-1 bioavailability, decreased with age, which surprised the researchers, and is not positively associated with absolute levels of free IGF-1. However, higher levels of PAPP-A2 cleave IGFBP-3 resulting in lower levels of intact IGFBP-3, and consequently, increasing the percentage of free to total IGF-1. This demonstrates that PAPP-A2 is a key regulator of IGF-1 bioavailability on a population-wide scale.

Impact: This research may help endocrinologists create unique, targeted treatment for children with PAPPA2 mutations and could help stratify patients with potential risk factors, such as IGF-1 resistance due to increased binding of IGF-1, associated with severe growth and height disorders. See adjoining study below.

Watch: Video interview with Dr. Dauber

ABSTRACT 2: Presented on Saturday, March 23, at 12:45 p.m. CST

Electronic health records can alert physicians to patients who could benefit from genetic testing to identify severe growth disorders

Program: Growth, puberty, and insulin action and resistance

Session OR07-6: Integrating Targeted Bioinformatic Searches of the Electronic Health Records and Genomic Testing Identifies a Molecular Diagnosis in Three Patients with Undiagnosed Short Stature

Background: Despite referrals to pediatric endocrinologists and extensive hormonal analysis, children with short stature due to a genetic cause, may not receive a diagnosis. Electronic health records may help identify patients – based on associated phenotypes and clinical parameters – who could benefit from genetic testing.

Study results: Researchers from three children’s hospitals – Boston Children’s Hospital, Children’s Hospital of Philadelphia and Cincinnati Children’s Hospital Medical Center – gathered data, starting small, with a known variable, or phenotype, associated with severe growth disorders: insulin-like growth factor 1 (IGF-1) resistance. A targeted bioinformatics search of electronic health records led the team to identify 39 eligible patients out of 234 candidates who met the criteria for a possible genetic-linked growth disorder. Participants were included if their height fell below two standard deviations for age and sex and if their IGF-1 levels rose above the 90th percentile. Patients who had a chronic illness, an underlying genetic condition or precocious puberty were excluded. Whole-exome sequencing (WES) was performed on DNA extracted from willing participants, including 10 patients and their immediate family members. The research team identified new genetic causes in three out of 10 patients with severe growth disorders, who were previously missed as having a genetic-linked growth disorder.

Note: Two patients had two novel IGF1R gene variants; a third had a novel CHD2 variant (p. Val540Phe). The two patients with IGF1R variants had a maternally inherited single amino acid deletion (p.Thr28del) and a novel missense variant (p. Val1013Phe).

Impact: Similar EHR algorithms can be replicated to identify pediatric patients at risk for or thought to have other genetic disorders, while expanding genetic research and improving patient care.

Watch: Video interview with Dr. Dauber

POSTER: Presented on Monday, March 25, at 1 p.m. CST

Electronic health record alerts could help detect Turner syndrome, shorten diagnostic odyssey for girls born with a missing or partially-deleted X chromosome

Program: Session P54. Pediatric puberty, ovarian function, transgender medicine and obesity

Poster Board #MON-249: Algorithm-Driven Electronic Health Record Notification Enhances the Detection of Turner Syndrome

Background: Turner syndrome (TS) results from a complete or partial loss of the second X chromosome and affects about one in every 2,500 female births. TS is common in females with unexplained short stature, but the diagnosis is often not made until late childhood (8-9 years), leading to delays in treatment and screening for comorbidities, such as heart conditions, chronic ear infections, vision problems and challenges with non-verbal learning. Using electronic health record (EHR) alarms can help clinicians screen for and diagnose TS patients earlier in life.

Study results: Researchers from Cincinnati Children’s Hospital Medical Center searched EHRs for female patients with idiopathic short stature who met the team’s selection criteria: Their height fell below two standard deviations from the mean for age as well as one standard deviation below the mid-parental height, had a BMI greater than 5 percent and did not have a chronic illness. The search produced 189 patients who met the diagnostic criteria, 72 of whom had not received prior genetic testing. Out of genetic samples available, 37 were compatible for a microarray analysis – which helped the team identify two cases of TS and a third chromosomal abnormality, all of which were missed by routine clinical evaluation.

Impact: DNA samples may not be available for all patients, but clinicians and researchers can identify and integrate tools into EHR’s – creating their own algorithms. An example includes setting up alerts for specific growth parameters, which helps identify and screen patients for TS.

The abstracts Dr. Dauber and his team discuss at ENDO 2019 support ongoing research, including a partnership among four leading children’s hospitals – Children’s National Health System, Boston Children’s Hospital, Children’s Hospital of Philadelphia and Cincinnati Children’s Medical Center – funded by an R01 grant to study how electronic health records can detect and identify novel markers of severe growth disorders.

The researchers hope their findings will also identify and help screen for comorbidities associated with atypical growth patterns, supporting multidisciplinary treatment throughout a child’s life. The study started in August 2018 and includes three sets of unique diagnostic criteria and will analyze WES from dozens of patients over five years.

Read more about Dr. Dauber’s research presented at ENDO 2019 in Endocrine Today and watch his video commentary with Medscape.