|Project Number:||1X01 HL 140518-01||Contact PI / Project Leader:||Daniela Luquetti|
|Title:||Craniofacial Microsomia: Genetic Causes and Pathway Discovery||Awardee Organization:||Seattle Children's Hospital|
DESCRIPTION (provided by applicant):
Craniofacial microsomia (CFM), also termed hemifacial microsomia or oculo-auricular-vertebral spectrum, is the third most common congenital craniofacial condition. CFM has an estimated birth prevalence in the US of 1 in 3,500-5,600, which is similar to conditions such as cystic fibrosis (1 in 3,700) and neurofibromatosis (1 in 4,200). CFM comprises a variable phenotype, and the most common features include malformations of the ear (i.e. microtia) and lower jaw (i.e. mandibular hypoplasia) on one or both sides. The etiology of CFM is largely unknown; however the presence of multiple cases within families, mouse models with CFM malformations and the increased risk of CFM in some ethnicities suggest that genetic variants contribute to its occurrence. Although chromosomal abnormalities have been associated with CFM, only three causative genes have been identified in few cases: HOXA2, FGF3, and MYT1. Our goal in this proposal is to identify coding and non- coding variants that are genetic risk factors to CFM by performing whole-genome sequencing (WGS) of case- parent trios with CFM. We propose to perform whole genome sequencing on DNAs from 105 trios (individuals with CFM and their parents or affected relatives in multi-affected families) to identify candidate genes with rare de novo and inherited variants. Our hypothesis is that CFM is caused by rare new and inherited DNA variation in gene(s) related to the craniofacial development. We will analyze the data on rare de novo coding and non- coding variants. Recognizing reduced penetrance in CFM, our analysis will include analyses for variants in a dominant inheritance with incomplete penetrance model. Our approach incorporates detailed phenotype, clinical characterization, and family history for each individual. We will also integrate the WGS data with our data on gene expression from murine embryonic pharyngeal arch and external ear human embryonic tissue to ascertain tissue specific expression at the relevant time of the development of tissues in CFM. Our statistical power by sampling patients with familial and severe disease who are most likely to have a high genetic loading. CFM represents an ideal condition in which to identify susceptibility variants because it is (1) relatively rare and represents more extreme selection under a liability threshold model, (2) distinctive, (3) stable, and (4) This study will be conducted by an interdisciplinary team with complementary expertise in clinical aspects of CFM, clinical genetics, genomics, and bioinformatics. Successful completion of this proposal will advance knowledge in the genetic architecture of susceptibility to CFM and will provide insight about the biological mechanisms underlying craniofacial development. The phenotypic and genomic data will be fully integrated into the Kids First Data Resource and available to all qualified investigators. The long-term goal of this project is to identify specific genetic risk factors to improve genetic counseling, enable tailored clinical care, and to provide more accurate prognosis. often familial (20-40% of cases). PUBLIC HEALTH RELEVANCE: Craniofacial microsomia (CFM) is the third most prevalent condition that affects craniofacial development; however, the cause of CFM is unknown for most affected individuals. We have established a cohort through previous studies and collected DNA to identify the genetic contributions to CFM, which could facilitate diagnosis, tailored treatment and guide prevention strategies. The results from the proposed study have potential to further research on the etiology of other craniofacial disorders, and the pathogenesis of typical and atypical craniofacial development.