Introduction
Myelomeningocele is the most common neural tube defect (NTD), with a
prevalence of 3.2 per 10,000 births (Zaganjor et al., 2016). Affected
people are born with both meninges and spinal cord exposed through a
cleft in their vertebral column. People with myelomeningocele ordinarily
survive with the appropriate medical care but frequently live with
comorbidities such as Chiari malformation type II, sensory and motor
issues below the opening, and more (Copp et al., 2015).
Myelomeningocele is a multifactorial disease, with evidence suggesting
genetic susceptibilities play an important contributing role. Although
maternal folate deficiency and gestational diabetes are both risk
factors for NTDs, not all cases are explained by the environment of the
fetus. One study indicates that only 27.6% of
myelomeningocele cases can be
attributed to known risk factors (Agopian, Tinker, Lupo, Canfield, &
Mitchel, 2013). In fact, the heritability estimate of myelomeningocele
in humans is 0.6 (Woolf, 1975). There is an increasing number of
naturally occurring and lab-generated knockout mice with disruption of
at least 372 genes exhibiting NTD phenotypes in mouse models (Salbaum &
Kappen, 2010), illustrating the role that genetic mutation can have on
this family of disorders in vertebrates.
One possible pathway affected in people with myelomeningocele is planar
cell polarity (PCP). Aside from controlling other morphological events
across many species (Henderson, Long, & Dean, 2018), PCP regulates
convergent extension during embryogenesis which is necessary for correct
neural tube closure in vertebrates (Nikolopoulou, Galea, Rolo, Greene,
& Copp, 2017). In humans with NTDs, variants predicted to impair
protein function have been found in PCP pathway genes (Juriloff &
Harris, 2012). PCP is one branch of the larger group of WNT signaling
pathways (Chu & Sokol, 2016; Wu & Mlodzik, 2017; W. Yang et al.,
2017). Some genes from the WNT signaling pathways outside PCP are also
implicated in the development of NTDs in humans (Allache et al., 2015;
Lei et al., 2015).
Given previous evidence that genes involved in WNT signaling contribute
to NTDs in humans and model organisms, we aimed to comprehensively
evaluate rare, likely deleterious, coding variants within all WNT
signaling pathway genes. To do so, we leveraged a gene-based mutational
burden analysis, which provides the following advantages: it does not
require multiplex family data, it lends potentially more power than
single-variant approaches, and it has been successfully applied to the
publicly-available datasets we chose as controls in another study (Guo,
Plummer, Chan, Hirschhorn, & Lippincott, 2018). We hypothesize that
genes within the WNT signaling pathways harbor rare deleterious variants
(RDVs) that are overrepresented in myelomeningocele subjects.