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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-015-1606-x) contains supplementary material, which is available to authorized users.
Highlights
Orofacial clefts (OFCs) are characterized by orofacial dysmorphism that may extend from the oral cavity to the whole face, involving the eyes and ears in the most severe cases
We report a comprehensive bioinformatics and statistical analysis to identify candidate causative genes involved in OFCs by analyzing common copy number variants (CNVs) regions shared by OFC patients retrieved from DECIPHER and ECARUCA databases
Craniofacial abnormalities including OFCs are among the most significant phenotypes where large CNVs are involved in the etiology (Cooper et al 2011)
Summary
Orofacial clefts (OFCs) are characterized by orofacial dysmorphism that may extend from the oral cavity to the whole face, involving the eyes and ears in the most severe cases. Due to the relatively low number of OFC patients exhibiting CNVs that are available in individual research centers, a systematic CNV study of a large number of OFC patients has not yet been performed to investigate the etiology of OFCs. Recently, new consortia have been organized to create comprehensive databases of clinical case data by combining the resources from different medical centers worldwide. Ecaruca.net) is another database that provides both clinical and molecular details on unbalanced chromosomal aberrations, recording over 4800 clinical cases so far (Vulto-van Silfhout et al 2013) These publicly accessible databases provide rich resources to systematically study genetic mechanisms in a large number of CNV patients with OFCs. Here, we report a comprehensive bioinformatics and statistical analysis to identify candidate causative genes involved in OFCs by analyzing common CNV regions shared by OFC patients retrieved from DECIPHER and ECARUCA databases. This study identifies two previously known OFC genes and several novel candidate OFC genes
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