Discovery of regulatory and cryptic splice-impacting variants in facial ectoderm-expressed genes: a secondary analysis of GMKF orofacial cleftdata.

PROJECT SUMMARY/ABSTRACT This proposal centers around a secondary analysis of available whole genome sequencing data from the Gabriella Miller Kid's First orofacial cleft cohorts. Non-syndromic orofacial clefts, such as cleft lip/palate, are among the most common human birth defects, yet our understanding of the significant genetic component underlying the risk of being born with this anomaly is far from complete. The proposed research plan involves a two-pronged targeted analysis to identify genetics variants that is unique in its approach. The first aim seeks to catalogue variants located within regulatory elements specifically active in the facial ectoderm, while the second aim investigates deep intronic variants in ectodermally expressed genes for their potential to disrupt correct mRNA splicing. The unique focus on ectodermal gene contributions is based on strong demonstrable biological data for this cell population being a major contributor to orofacial cleft risk. These analyses hold the promise of providing unique insight into the genetic architecture of non-syndromic cleft lip/palate.