Kids First-KOMP2: Nomination Process for 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. You are invited to nominate variants identified through your analysis of Kids First datasets, or identified from another dataset and substantiated in a Kids First dataset, for mouse model production and phenotyping. Investigators may nominate more than one variant (i.e. propose the creation and phenotyping of multiple mice), when justified.
Nominations will be reviewed administratively by a subcommittee of NIH staff from the Kids First Working Group. Variants will be prioritized based on the strength and breadth of the supporting evidence. Decisions will be finalized in consultation with KOMP2 staff.
In no more than three pages per nominated variant, please address the following. If you are proposing multiple variants or a gene network, please describe this as concisely as possible:
- Kids First datasets used and disease or syndrome investigated.
- Variant(s) you are proposing to model, as applicable, the variant class (e.g. coding, SV-duplication, SV-deletion, CNV, etc.), human genomic coordinates and genomic assembly, transcript ID, DNA change, inheritance, disease with OMIM ID and corresponding mouse ortholog, genomic coordinates, and genomic assembly (if known).
- Phenotype of the human case(s) associated with the variant.
- The predicted mouse phenotype associated with the variant and the predicted value of the mouse model and/or phenotype data for your study (e.g. pathogenicity confirmation, further mechanistic study, etc.) and studies you plan to undertake using the model, if any.
- Supporting evidence that this variant is associated with this phenotype (e.g., expression levels of downstream genes that may be associated with the phenotype). Summarize findings from bioinformatic analyses, literature review, and entries in relevant databases, including existing animal models (e.g. IMPC, MGI, Zfin, Xenbase).
- Provide any additional justification that should be considered.
Additional information may be requested after preliminary review.
Variant nominations will be accepted on the following dates for selection on a semi-rolling basis:
- January 18, 2019
- February 22, 2019
- April 5, 2019
Please submit variant nominations by email to firstname.lastname@example.org with the Subject Line: “Kids First KOMP2 Nomination."
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.
Projects Selected for this Opportunity:
- Dataset: “GMKF: Kids First Pediatric Research Program on Congenital Cranial Dysinnervation Disorders and Related Birth Defects” (dbGaP accession number: phs001247)
PI: Elizabeth Engle, Boston Children's Hospital
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 (GMKF) research program. As a next step in this partnership, the Engle Lab will collaborate with the Kids First-KOMP2 project 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.
- Dataset: “Kids First: Pediatric Research Project on the Genomic Analysis of Congenital Diaphragmatic Hernia” (dbGaP accession number: phs001110)
PI: Gabrielle Kardon, University of Utah
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.
This page last reviewed on February 7, 2019