Accelerating Discovery and Characterization of Genetic Variants Underlying Dental, Oral, and Craniofacial Diseases and Conditions

September 2019

Translational Genetics and Genomics Program

Translational Genomics Research Branch

Division of Extramural Research

Goal

This initiative aims to improve human dental, oral, and craniofacial (DOC) health by accelerating discovery and characterization of genetic variants underlying a broad range of DOC diseases and conditions, and the genes bearing them (DOC genes and variants). The knowledge obtained will shed light on DOC disease etiologies, and inform prognoses, diagnoses, and treatments of diseases. In addition, knowledge of shared genes and variants between DOC and other body parts will contribute to understanding biology of the human body as a whole, which in turn, will help improve DOC and overall health.

Background

Considerable progress has been made with discovering DOC genes and variants. However, many DOC diseases, including cleft lip/palate and craniosynostosis, cannot be fully explained by their known underlying variants. Moreover, there are DOC diseases and conditions with a suspected genetic component not yet associated with any gene. A search of Mendelian Inheritance in Man (OMIM) reveals that currently, there are ~360 DOC phenotypes with associated genetic variants, and another ~100 suspected monogenic, oligogenic, or polygenic DOC phenotypes. At the same time, OMIM continues to record newly reported phenotypes, likely adding to the pool of DOC phenotypes with a suspected genetic component. Thus, many DOC genes and variants still await discoveries. Further, there has not been sufficient functional characterization and mechanistic study of DOC genes and variants, work that is critical to understand DOC disease etiology.

Gaps and Opportunities

In the past 10 years or so, genomewide sequencing and data analysis methods have matured for rapid discovery of disease-causing genetic variants. Concurrently, technologies such as CRISPR/Cas9, iPS cells, and cutting-edge in silico approaches have made functional characterization and mechanistic study of genes and genetic variants more feasible. Now is time to prioritize the Institute’s genetics and genomics portfolio for more projects that use genome-wide sequencing and advanced technologies for DOC genes and variants discovery, characterization, and mechanistic study. This initiative will also encourage successful GWAS projects to proceed with investigation of gene function and disease etiology, while efforts to discover novel DOC genes and variants continue.

Current Portfolio:

• NIDCR supports Genetics of Dental Enamel Formation (R01-DE015846), Rapid Identification and Validation of Human Craniofacial Development Genes (U01-DE024443), and Forward Genetic Analysis of Congenital Craniofacial Malformations (R01DE027091), projects entailing sequencing to discover disease variants and functional characterization of discovered variants.
• NHGRI, NHLBI, and NEI support Centers for Mendelian Genomics, which focuses on novel gene and variant discovery underlying any human disease using established pipelines that mainly use whole exome sequencing. The program itself does not focus on functional study of genetic variants.
• NIH Common Fund Undiagnosed Diseases Network (UDN) supports disease gene discovery and characterization. This program is ending is three years.

This initiative is intended to support projects using genome-wide nucleic acid sequencing and analysis leading to the discovery of novel DOC genes and variants or novel sub-clinical phenotypes previously not associated with any known DOC variant, with or without complementary genomic approaches. Genetic variants to be discovered include single nucleotide variants (SNVs) or structural variants (SVs) affecting the coding region, non-coding region, or the entirety of a gene that occur in germ cells or somatic cells. Applications should also propose to characterize functional significance of discovered genes and variants using animal models, in vitro systems, in silico methods, or other approaches. Concurrent with functional characterization or under a separate aim, experimental demonstration and/or analytical inference that can shed light on mechanistic aspects of disease etiology is highly encouraged. Under this initiative, genome-wide association studies (GWAS) will not be supported.

References

• Yang J, et al. (2015) The dentin phosphoprotein repeat region and inherited defects of dentin. Mol Genet Genomic Med. Sep 7;4(1):28-38.
• Mukherjee K, et al. (2016) Actin capping protein CAPZB regulates cell morphology, differentiation, and neural crest migration in craniofacial morphogenesis. Hum Mol Genet. Apr 1;25(7):1255-70.
• Posey JE, et al. (2019) Insights into genetics, human biology and disease gleaned from family based genomic studies. Genet Med. 21(4):798-812.
• Ramoni RB, et al. (2017) The Undiagnosed Diseases Network: Accelerating Discovery about Health and Disease. Am J Hum Genet. 100(2):185-192.