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Burden of Rare Deleterious Variants in WNT Signaling Genes Among 511 Myelomeningocele Patients
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  • Luke Hebert,
  • Paul Hillman,
  • Craig Baker,
  • Michael Brown,
  • Allison Ashley-Koch,
  • James Hixson,
  • Alanna Morrison,
  • Hope Northrup,
  • Kit Sing Au
Luke Hebert
University of Texas Health Science Center at Houston

Corresponding Author:[email protected]

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Paul Hillman
University of Texas Health Science Center at Houston
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Craig Baker
University of Texas Health Science Center at Houston
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Michael Brown
University of Texas Health Science Center at Houston
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Allison Ashley-Koch
Duke University Medical Center
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James Hixson
University of Texas Health Science Center at Houston
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Alanna Morrison
University of Texas Health Science Center at Houston
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Hope Northrup
University of Texas Health Science Center at Houston
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Kit Sing Au
University of Texas Health Science Center at Houston
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Abstract

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.