Genetic basis of craniofacial malformations. (360G-Wellcome-093329_Z_10_Z)

1. Prospective ascertainment of patients requiring craniofacial surgery at the four participating centres. We will aim to recruit a minimum of 150 patients (with parents) annually. 2. Identification of new monogenic causes of craniofacial malformation within this cohort using massively parallel sequencing. We will use 16 lanes of Illumina-based sequencing of captured whole exomes in patients or parents chosen because of a combination of positive family history, evidence of progressive feature s, distinctive phenotype or suspected de novo mutation. We will use bioinformatic analysis, including knowledge of gene expression and protein interaction networks affected by known craniofacial mutations, to prioritise genes for further sequencing. 3. We will assess the genetic impact of candidate mutations by DNA sequencing and analysis of exon copy number in the larger cohort, to establish the presence of mutations in the wider sample resource, and determine mutation spectrum, prevalence an d genotype-phenotype correlation. 4. We will undertake studies on the expression of identified genes in murine cranial sutures or other craniofacial structures, and relevant functional assays. 5. As a long-term goal we wish to acquire surgical and developmental outcome data linked to genotype.