Discussion
Exomes of the myelomeningocele cases compared to gnomAD references revealed nominally significant disruption among genes that function in WNT trafficking, PCP, WNT/β-catenin signaling, and WNT/Ca2+ signaling. Our control value estimation method overestimates the number of RDVs in the gnomAD reference population, so protective variants are likely also overestimated. Therefore, we focus on genes with an odds ratio greater than one, which indicates a risk for myelomeningocele. To remain conservative in our conclusions, we do not evaluate genes whose mutational burden indicates a protective effect, marked by an odds ratio less than one. All nominally significant genes with an odds ratio greater than one are included in Table 1, but our discussion further focuses on ten genes that have either been associated with NTD phenotypes, were expressed during closure of the caudal human neural tube, or harbored individual variants that were much more common in the cases than the controls. Nominally significant genes meeting one or more of these criteria are:PORCN , CPE , FUZ , TNRC6B , DVL2 ,DDB1 , PRICKLE2 , CDH2 , PPP2R1A , andSOSTDC1 . For clarity, we organize each of these ten genes based on their known role in WNT trafficking (Fig 3), the PCP pathway (Fig 4), the canonical β-catenin pathway (Fig 5) or noncanonical Ca2+ WNT signaling pathway (S1 Fig). These figures provide visual references for these pathways with special attention drawn to the translational products of the ten disrupted genes mentioned above (Nusse & Clevers, 2017).