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).