Kids First-KOMP2: Precision Modeling of Pediatric Conditions Pilot 

The NIH Gabriella Miller Kids First Pediatric Research Program (Kids First) and the Knockout Mouse Phenotyping Program (KOMP2) are collaborating on a pilot project to develop mouse strains to study, phenotype, and validate coding and noncoding genetic variants (e.g. missense, structural variants, copy number variants, INDELS, frame shifts) identified from Kids First datasets. 

The Kids First and KOMP2 leadership teams hosted a webinar titled “Precision Modeling of Pediatric Conditions” on September 21, 2018 to provide information about this collaboration. Investigators can watch the webinar and review PowerPoint slides from the presentations for details about this opportunity. 

To learn more about KOMP2’s pipeline visit, For technical questions related this Kids First-KOMP2 collaboration contact: Updates about this project will be announced once information become available. 

Projects Selected for this Opportunity: 

  • Phenotypic characterization of novel candidate risk genes of congenital diaphragmatic hernia using in mice models
    Investigation Team: Wendy K Chung and Yufeng Shen, Columbia University 
    Project Narrative: Congenital diaphragmatic hernia (CDH) is a severe birth defect affecting about 1 in 3000 live births. Previous studies have found CDH is genetically heterogeneous. Our team have analyzed over 700 CDH patient-parents trios with whole genome sequencing data generated by the Gabriella Miller Kids First Pediatric Research Program (Kids First). We identified candidate risk genes based on deleterious de novo variants (single nucleotide variants, short insertions and deletions, and copy number variants), and then prioritized candidate genes by integrating statistical evidence with gene expression patterns during embryonic development. In this collaboration with the Knockout Mouse Phenotyping Program (KOMP2) and Kids First, we aim to functionally characterize the phenotypes of selected novel CDH candidate genes (RYBP, CDC42BPB, AGO1, and CNOT1) in mouse models. Dr. Steve Murray and his team at The Jackson Laboratory will create the mouse models and perform detailed phenotyping. We anticipate this collaboration will functionally validate some of the candidate genes and expand our understanding of disease etiology of CDH and associated congenital anomalies.
    Kids First Dataset Used in This Project: Pediatric Research Project on the Genomic Analysis of Congenital Diaphragmatic Hernia (dbGaP accession number: phs001110

  • Modeling Enchondroma Development in Mice: Testing the Role of KDM4C in Ollier Disease
    Investigation Team: Nara Sobreira (PI) & Sarah Robbins, Johns Hopkins University
    Project Narrative: Ollier disease is a rare disorder characterized by the development of multiple enchondromas. Patients with Ollier disease are also at increased risk for cancer, mainly chondrosarcoma, brain, and gonadal cancers. Though somatic variants in IDH1 and IDH2 are associated with Ollier disease, to date, no germline variants have been described. As part of the Gabriella Miller Kids First Research Program, we performed WGS on a cohort of patients with Ollier disease and identified rare, heterozygous, germline variants in genes in the HIF-1 pathway in 33% of the patients. One patient had compound heterozygous variants in KDM4C, each inherited from one of his parents. By immunoblot analysis of the patient’s fibroblast, we have established that these variants lead to loss of function at normoxia and hypoxia. To prove that these variants are responsible for tumorigenesis in this patient, we are partnering with the Kids First-KOMP2 project. Using CRISPR/Cas9-gene editing, the Jackson laboratory team will develop a compound heterozygous mouse model and a homozygous mouse model for each of the variants identified in the patient with Ollier disease. Together, we will develop a rigorous anatomical phenotyping protocol that will investigate the enchondroma and cancer development in these mouse models. We anticipate that these mouse models will enable future studies on the pathophysiology of enchondroma formation and on possible pharmacological treatments for patients with Ollier disease.  
    Kids First Dataset Used in This Project: Genome-wide Sequencing to Identify the Genes Responsible for Enchondromatoses and Related Malignant Tumors  (data for this project are not yet available for access)
  • Deep Phenotypic Characterization of a Noncoding Duplication Underlying Congenital Facial Weakness 
    Investigation Team: Elizabeth Engle (PI) & Arthur Lee, Boston Children's Hospital
    Project Narrative: The Engle lab studies the genetic basis of congenital cranial dysinnervation disorders (CCDDs) which are a set of neurodevelopmental diseases that can affect facial and eye movements. The Engle lab has collected, sequenced and analyzed over 899 whole genome sequences through the Gabriella Miller Kids First research program (Kids First). As a next step in this partnership, the Engle Lab will collaborate with the the Kids First and the Knockout Mouse Phenotyping Program (KOMP2) to study the impact of structural variation on CCDDs, using the mouse as a model system. Together we plan to generate mutant mice bearing a 56 kb tandem duplication of a noncoding region that segregates in a large CCDD family and perform behavioral, anatomical, and molecular phenotyping using state-of-the-art technologies.
    Kids First Dataset Used in This Project: GMKF: Kids First Pediatric Research Program on Congenital Cranial Dysinnervation Disorders and Related Birth Defects (dbGaP accession number: phs001247)
  • In vivo Modeling for a Novel Tubulinopathy 
    Investigation Team: Elizabeth Engle (PI) & Julie Jurgens, Boston Children's Hospital
    Project Narrative: Ocular congenital cranial dysinnervation disorders (CCDDs) are rare pediatric disorders of neurodevelopment defined by defective innervation of the extraocular muscles, which are responsible for eye movement. Although ocular CCDDs are often inherited, the genetic basis for many of them remains unknown. Through the Gabriella Miller Kids First Pediatric Research Program, the Engle lab has performed whole genome sequencing of 899 individuals with unsolved CCDDs and their families, enabling identification of a novel candidate missense variant in a tubulin isotype in one of these disorders. Tubulin isotypes have high homology to one another and modeling missense tubulin variants in mouse can be challenging. Thus, the Engle lab is teaming up with Kids First and the Knockout Mouse Phenotyping Program (KOMP2) to develop and phenotype a knock-in mouse model. Dr. Kent Lloyd’s team at UC Davis is generating this mouse model and will perform detailed anatomical and behavioral phenotyping, which will be followed by targeted phenotyping of cranial nerve development in the Engle lab. We anticipate that this collaboration will validate a strong novel candidate genetic variant and expand our fundamental understanding of mechanisms underlying ocular CCDDs and other tubulinopathies, enabling improved genetic counseling and care for patients with these conditions. 
    Kids First Dataset Used In This Project: GMKF: Kids First Pediatric Research Program on Congenital Cranial Dysinnervation Disorders and Related Birth Defects (dbGaP accession number: phs001247)
  • Development of Mouse with 343bp Deletion in Gata4 Intron 2 to Test Role in CDH and CHD
    Investigation Team: Gabrielle Kardon (PI) & Eric Bogenschutz, University of Utah
    Project Narrative: Congenital Diaphragmatic Hernias (CDHs) are common and often lethal birth defects in which an aberrantly developed diaphragm allows abdominal contents to herniate into the thoracic cavity. Using whole genome sequencing of CDH children and their healthy parents, we have discovered an inherited noncoding variant, in which a 350 base pair deletion disrupts a putative enhancer of Gata4, a gene highly associated in humans with CDH and functionally demonstrated in mouse to cause CDH. We hypothesize that this deletion leads to reduced Gata4 expression, a highly dosage sensitive gene, and creates a sensitized genetic background for development of CDH. To test this, we will generate mice with this 350 base pair deletion and test whether this creates a sensitized genetic background for development of CDH. If true, this will provide the first evidence that noncoding genetic elements contribute to the etiology of CDH. We will generate the relevant mutant mice in collaboration with the KOMP2 DTCC Consortium at The Centre for Phenogenomics using CRISPR/Cas9-endonuclease technologies.
    Kids First Dataset Used in This Project: Kids First: Pediatric Research Project on the Genomic Analysis of Congenital Diaphragmatic Hernia (dbGaP accession number: phs001110)
  • Noncoding De Novo Variants in Congenital Heart Disease: From Predicted Pathogenicity to Model Organism
    Investigation Team: Bruce Gelb (PI) & Felix Richter, Icahn School of Medicine at Mount Sinai on behalf of the Pediatric Cardiac Genomics Consortium
    Project Narrative: Congenital heart disease (CHD) represents a growing disease burden and is primarily genetic. CHD is typically sporadic with approximately 8% explained by damaging coding de novo variants. Building on these data, we compared noncoding de novo variants in 800 parent/affected-child trios (750 from Gabriella Miller Kids First Pediatric Research Program) to controls using variant-level scores that predict cardiac regulatory disruption. We discovered a burden of predicted damaging variants in cases, including a noncoding de novo deletion in BCOR and a noncoding de novo single base change in GATA4. A critical next step to establish pathogenicity is testing if these mutations cause CHD in mice. To model these variants, we are working with experts in the latest CRISPR/cas9 technology through the Kids First-KOMP2 collaboration. Kent Lloyd’s group from University of California, Davis will create mice with the BCOR deletion, and Lauryl Nutter’s team from The Center for Phenogenomics at Toronto’s Hospital for Sick Children will introduce the GATA4 variant into mouse germlines. Further leveraging the Kids First-KOMP2 partnership, mutant mice will be phenotyped through extensive imaging and pathology protocols. This work is crucial to improving our understanding of how noncoding regions, which account for 99% of the human genome, contribute to birth defects like CHD.
    Kids First Dataset Used in This Project: Discovery of De Novo and Inherited Mutations that Cause Prevalent Birth Defects and Discovery of the Genetic Basis of Structural Heart and Other Birth Defects (dbGaP accession number: phs001138)

This page last reviewed on September 16, 2019