Craniofacial Microsomia: Genetic Causes and Pathway Discovery

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PROJECT SUMMARY Craniofacial microsomia (CFM) is a common congenital condition (1:3,500) that affects the facial skeleton, ears, and facial nerve among other facial and extracranial malformations. As a result, children with CFM frequently require multiple interventions to restore their airway, feeding, hearing, and facial symmetry. The lifelong health care needs associated with CFM substantially impact families, the health care system, and society. The genetic risk factors for this condition remain largely unknown and large multi-center studies addressing this fundamental gap in knowledge have not yet been conducted. In this application, we propose to study the genetic etiology of CFM. Our long term objective is to identify the genetic and non-genetic risk factors that contribute to CFM and evaluate the affected genetic pathways. We have identified 18 candidate genes for CFM in our study of 29 trios (affected individual with CFM and non-affected parents). Based on our preliminary findings and using the FACIAL network, an established network funded by the NIH specifically designed to study CFM, we propose to conduct the following studies: Aim 1) define genes and gene pathways whose expression is disrupted in the developing facial tissue that contributes to the CFM phenotype; Aim 2) identify new candidate genes for CFM by using whole genome sequencing in 170 trios from banked samples (n=70) and prospective enrollment (n=100); and Aim 3) detect mutations in 50 candidate genes identified in our previous genetic studies in CFM and in Aims 1 and 2 using targeted capture sequencing on samples from 490 individuals with CFM. The combination of deep high throughput sequencing and gene expression studies in relevant tissues from human and animal models will facilitate the identification of meaningful genetic causes for this disorder. Our multidisciplinary FACIAL network has the infrastructure to investigate the genetic complexity in CFM. Including both national and international sites, which have a higher prevalence of CFM, the FACIAL network has the ability to collect high-quality data on a large (n=660) and well-characterized population. We expect that our proposed studies will identify genes that cause CFM and generate insights into the pathways that regulate craniofacial development, thus providing useful information for the study of CFM and other craniofacial disorders. This research will positively impact health care for this population by identifying options for molecular diagnosis, precise family and reproductive counseling, and for tailored clinical management and primary prevention strategies for high-risk populations. This is of highest relevance to the NIDCR mission to improve craniofacial health through research.