title: Systematic analysis of copy number variants of a large cohort of orofacial cleft patients identifies candidate genes for orofacial clefts.
abstract: Orofacial clefts (OFCs) represent a large fraction of human birth defects and are one of the most common phenotypes affected by large copy number variants (CNVs). Due to the limited number of CNV patients in individual centers, CNV analyses of a large number of OFC patients are challenging. The present study analyzed 249 genomic deletions and 226 duplications from a cohort of 312 OFC patients reported in two publicly accessible databases of chromosome imbalance and phenotype in humans, DECIPHER and ECARUCA. Genomic regions deleted or duplicated in multiple patients were identified, and genes in these overlapping CNVs were prioritized based on the number of genes encompassed by the region and gene expression in embryonic mouse palate. Our analyses of these overlapping CNVs identified two genes known to be causative for human OFCs, SATB2 and MEIS2, and 12 genes (DGCR6, FGF2, FRZB, LETM1, MAPK3, SPRY1, THBS1, TSHZ1, TTC28, TULP4, WHSC1, WHSC2) that are associated with OFC or orofacial development. Additionally, we report 34 deleted and 24 duplicated genes that have not previously been associated with OFCs but are associated with the BMP, MAPK and RAC1 pathways. Statistical analyses show that the high number of overlapping CNVs is not due to random occurrence. The identified genes are not located in highly variable genomic regions in healthy populations and are significantly enriched for genes that are involved in orofacial development. In summary, we report a CNV analysis pipeline of a large cohort of OFC patients and identify novel candidate OFC genes.
authors.affiliation: Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.|Medical Genetic Unit, Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Conte
authors.affiliation: Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Oti
authors.affiliation: Faculty of Medical and Human Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Dixon
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Carine E L
authors.initials: CE
authors.lastname: Carels
authors.affiliation: Medical Genetic Unit, Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy. michele.rubini@unife.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Rubini
authors.affiliation: Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands. j.zhou@science.ru.nl.|Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. j.zhou@science.ru.nl.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Zhou
mesh_terms: D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D056915:DNA Copy Number Variations; D005145:Face / Q000002:abnormalities*; D020022:Genetic Predisposition to Disease; D006801:Humans; D010641:Phenotype