Lisa Harney will Present her Research on Thursday, 10-15-15
The role of copy number variation in cleft lip and palate.
L. A. Harney1,2,3, B. W. Darbro1,3, A. Long2, J. Standley1, A.M. Hulstrand2,3, H. Liu4, R.A Cornell3,4, D.W. Houston2,3, J. C. Murray1,3, J. R. Manak1,2,3
1) Department of Pediatrics, University of Iowa, Iowa City, IA; 2) Department of Biology, University of Iowa, Iowa City, IA; 3) Interdisciplinary Genetics Program, University of Iowa, Iowa City, IA; 4) Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA
Clefts of the lip and/or palate (CL/P) occur in about 1 in 700 live births. Categorized as non-syndromic (NSCL/P) or syndromic (SCL/P), individuals with NSCL/P have isolated clefts and account for about 70% of clefting cases whereas syndromic occurrences include additional cognitive or structural anomalies. Although genome-wide association, candidate gene, and animal model studies have been used to study CL/P, a largescale analysis to determine the contribution of copy number variation (CNV) to CL/P has yet to be performed. We performed the largest high resolution array-based comparative genomic hybridization study to date to identify copy number variants associated with NSCL/P in a cohort of 868 cases from the Philippines and 212 individuals with SCL/P of mixed ethnicities. A preliminary analysis is underway which prioritizes likely causative CN events for follow-up in zebrafish and frogs. Focusing on rare copy number losses, we identified 196 genes that were deleted in greater than one individual while 735 genes were deleted in a single case; collectively, the majority of genes were not previously implicated in clefting. After comparing the list of deleted genes to OMIM, DECIPHER, NCBI, and MGI databases, four were selected for functional follow-up in zebrafish. These genes, ISM1, PKP2, MYO5C and ULK4, are all novel clefting candidates, are overlapped by a CNV loss in greater than one individual, and appear in less than 1% of the cohort. Six additional genes identified have been previously implicated in clefting through association studies (NTN1, PCYT1A), variant analyses (ZNF750, CDH1, OFD1), or chromosomal microarrays (IMMP2L).Together, these studies will define the contribution of copy number variants to disease incidence of CL/P.