Craniofacial anomalies such as clefts of the lip and palate are common birth defects of complex etiology and comprise a large fraction of morbid human birth defects. They require surgical, nutritional, dental, speech, medical and behavioral interventions and impose a substantial economic and societal burden. Family and population studies have confirmed a genetic component underlying the most common form of clefting- isolated (or non-syndromic) clefting. However, despite decades of research, the precise genes involved in human clefting remain largely unknown or unconfirmed, making the understanding of the genetic basis of the disease virtually impossible. Recently, it has become practical to identify genes contributing to complex traits such as clefts by using a combination of extensive family collections, careful phenotyping, high-throughput genotyping, robust analytic strategies, fine structure mapping, mutation characterization and animal model verification. We will take advantage of our extensive experience in these areas to explore an innovative approach to gene finding by searching for genomic deletions or amplifications (called Copy Number Variants, or CNVs) that cause clefting using microarray-based Comparative Genomic Hybridization (aCGH). Deletions/amplifications of less than 1 Kb (which we call microCNVs) have been identified as causal events in Mendelian disorders;similarly, CNVs (which may vary in size between 1 Kb and many Megabases) also cause human disease (indeed, they are now considered to be common causes of disease). However, such genomic rearrangements have not yet been examined for a large cohort of cleft lip and palate patients. In this project, we will identify clefting-associated CNVs (as well as microCNVs) for both candidate gene and novel loci followed by developmental and functional validation studies of the genes within the CNVs (in the zebrafish model system) to identify the clefting-specific genes. Additionally, we will use an unprecedented microarray reuse protocol which allows 5 uses of an array without compromising the quality of the data. Together, these methods will enable large numbers of clefting samples to be analyzed rapidly at high resolution while minimizing cost. This study will provide a substantial opportunity to demonstrate how a complex genetic defect can have its component causes identified and understood as well as provide the basis for the development of cleft lip and palate diagnostic tools.

Public Health Relevance

Project Narrative (Relevance to Public Health) Cleft lip and palate is a common and debilitating birth defect that is oftentimes fatal due to an inability to feed. Despite decades of research, the underlying genetic basis for clefting remains largely unknown, impeding understanding of the disease process as well as effective treatment. In this proposal we will utilize an advanced genomics technique to identify deletions and amplifications in the genome (these genomic changes are now considered common disease-causing alterations) and explore how these abnormalities can cause clefting.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
Project #
Application #
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Harris, Emily L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Schools of Arts and Sciences
Iowa City
United States
Zip Code
Lansdon, Lisa A; Darbro, Benjamin W; Petrin, Aline L et al. (2018) Identification of Isthmin 1 as a Novel Clefting and Craniofacial Patterning Gene in Humans. Genetics 208:283-296
Brophy, Patrick D; Rasmussen, Maria; Parida, Mrutyunjaya et al. (2017) A Gene Implicated in Activation of Retinoic Acid Receptor Targets Is a Novel Renal Agenesis Gene in Humans. Genetics 207:215-228
Leslie, Elizabeth J; O'Sullivan, James; Cunningham, Michael L et al. (2015) Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders. Am J Med Genet A 167A:545-52
Lidral, Andrew C; Liu, Huan; Bullard, Steven A et al. (2015) A single nucleotide polymorphism associated with isolated cleft lip and palate, thyroid cancer and hypothyroidism alters the activity of an oral epithelium and thyroid enhancer near FOXE1. Hum Mol Genet 24:3895-907
Azaiez, Hela; Decker, Amanda R; Booth, Kevin T et al. (2015) HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice. PLoS Genet 11:e1005137
Peyrard-Janvid, Myriam; Leslie, Elizabeth J; Kousa, Youssef A et al. (2014) Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development. Am J Hum Genet 94:23-32
Brophy, Patrick D; Alasti, Fatemeh; Darbro, Benjamin W et al. (2013) Genome-wide copy number variation analysis of a Branchio-oto-renal syndrome cohort identifies a recombination hotspot and implicates new candidate genes. Hum Genet 132:1339-50
Bassuk, Alexander G; Muthuswamy, Lakshmi B; Boland, Riley et al. (2013) Copy number variation analysis implicates the cell polarity gene glypican 5 as a human spina bifida candidate gene. Hum Mol Genet 22:1097-111
de la Garza, Gabriel; Schleiffarth, Jack Robert; Dunnwald, Martine et al. (2013) Interferon regulatory factor 6 promotes differentiation of the periderm by activating expression of Grainyhead-like 3. J Invest Dermatol 133:68-77