Whole genome sequencing analysis of nonsyndromic craniosynostosis

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PI: Simeon Boyd. MD Project Abstract Craniosynostosis (CS) is a major structural birth defect characterized by the premature fusion of one or more cranial sutures that affects about 1 in 2,500 live births. Most CS cases present as nonsyndromic (NCS), an isolated birth defect classified according to the suture(s) involved. NCS is considered a heterogeneous multifactorial disease and primary prevention strategies for NCS are limited. The etiology of NCS is largely unknown; however, findings generated by genomic technologies have begun to narrow this knowledge gap. Using the specimen resources of our International Craniosynostosis Consortium and the National Birth Defects Prevention Study, we successfully conducted the first two genome-wide association studies (GWAS)s for sagittal NCS (sNCS) and metopic NCS (mNCS), performed next generation sequencing (NGS) of candidate loci for sNCS and mNCS, and completed whole exome sequencing (WES) of more than 240 case-parent trios, multiplex, and/or multigenerational families with NCS. These efforts have allowed us to identify robust associations to loci near BMP2, BBS9, and within BMP7, as well as rare variants in biologic plausible genes involved in skeletal development. With the support of grant X01 HL140535-01 from the Gabriella Miller Kids First Pediatric Research Program we have already completed the whole genome sequencing (WGS) of 321 case-parent trios and multiplex families with various types of NCS. In addition, samples from 31 of those families are currently in process of long-read WGS. We hypothesize that the analysis of WGS and its integration with our extant genomic data will identify novel genetic factors beyond those identified with GWAS’s that contribute to the etiology of NCS. In this application, we propose to elucidate the genetic factors that contribute to NCS by implementing an integrative genomic analysis of WGS in Aim 1. In Aim 2 we will comprehensively interrogate the genetic architecture of NCS to identify all possible causal candidate genes and loci for NCS by harmonizing and analyzing our existing genomic data accumulated from GWASs, WGS, WES, and NGS of affected families. In Aim 3 we will perform initial characterization of likely causative variants and will prioritize them for future molecular studies. Our extant genomic data represents one of the largest NCS data collections compiled and is an unparalleled resource for studying the genetic etiology of NCS. Our approach will lay the foundation for comprehensive integration of genomic data in order to identify candidate genes and loci and to pursue animal models of NCS in the future. Given our past accomplishments, experienced interdisciplinary research team, and substantial resources, we are well poised to achieve the aims of this proposal and provide critical insights into the etiology of NCS.