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202010 Screening and Functional Validation of Human Genomic Variants

Program seeks Council approval for an initiative titled “Screening and Functional Validation of Human Genomic Variants”.

Rapid advances in genotyping and DNA sequencing have led to the identification of genetic variants that are associated with a wide range of structural birth defects. Among others, the Gabriella Miller Kids First Pediatric Research Program (Kids First), the Center for Mendelian Genomics (CMG), Pediatric Cardiac Genomics Consortium (PCGC), Deciphering Developmental Disorders (DDD) and the Undiagnosed Disease Network (UDN) are generating large-scale clinical and genetic data from patients and their families with syndromic and organ-specific developmental disorders. Data generated through whole genome sequencing, SNP analysis, and whole-exome sequencing are available to the research community through several databases such as the Database of Genotypes and Phenotypes (dbGaP), the Kids First data Resource Portal, the European Genome-phenome Archive and ClinVar. Despite an explosion of data resources, researchers face a challenging gap between identifying sequence variations of potential interest and recognizing which of those variations have functional effects on the phenotype of interest. 

In order to pursue mechanistic studies of how specific genetic variants affect developmental pathways and gene networks leading to the observed phenotype, researchers must have effective methods to screen potential variants to identify causal variants. Faster, cheaper, and more accurate gene-to-function screens are critical for accelerating the translation of genomic findings into greater understanding of mechanisms of structural developmental disorders. The goal of this initiative is to promote screening, functional validation and characterization of structural birth defect associated genetic variants using in-silico tools, amenable animal models, in vitro systems or a combination of multiple tools and model systems. 

The proposed concept aligns with Theme 1 of the NICHD Strategic Plan: “Understanding the Molecular, Cellular, and Structural Basis of Development”. 

The concept also aligns with the DBSVB research priority on identification, validation, and functional characterization of human genetic variants associated with structural birth defects.

Program Contact

Mahua Mukhopadhyay
Developmental Biology and Structural Variation Branch (DBSVB)

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