Burden of Rare Deleterious Variants in WNT Signaling Genes Among 511
Genes in the noncanonical WNT signaling pathway controlling planar cell
polarity have been linked to the neural tube defect myelomeningocele. We
hypothesized that some genes in the WNT signaling network have a higher
mutational burden in myelomeningocele subjects than in control subjects.
Exome sequencing data from 511 myelomeningocele subjects was obtained
in-house and data from 29,940 ethnically matched subjects was provided
by version 2 of the publicly available Genome Aggregation Database. To
compare mutational burden, we collapsed rare deleterious variants across
each of 523 human WNT signaling genes in case and control populations.
Ten WNT signaling genes were disrupted with a higher mutational burden
among Mexican American myelomeningocele subjects compared to Hispanic
controls (Fishers exact test, P ≤ 0.05) and seven different genes were
disrupted among individuals of European ancestry compared to controls.
Gene ontology enrichment analyses indicate that genes disrupted only in
the Mexican American population play a role in planar cell polarity
whereas genes identified in both populations are important for the
regulation of canonical WNT signaling. In summary, evidence for WNT
signaling genes that may contribute to myelomeningocele in humans is
presented and discussed.