Abstract
Myelomeningocele (MMC) affects one in 1000 newborns annually worldwide and each surviving child faces tremendous lifetime medical and caregiving burdens. Both genetic and environmental factors contribute to disease risk but the mechanism is unclear. This study examined 506 MMC subjects for ultra-rare deleterious variants (URDVs, absent in gnomAD v2.1.1 controls that have Combined Annotation Dependent Depletion score ≥ 20) in candidate genes either known to cause abnormal neural tube closure in animals or previously associated with human MMC in the current study cohort. Approximately 70% of the study subjects carried one to nine URDVs among 302 candidate genes. Half of the study subjects carried heterozygous URDVs in multiple genes involved in the structure and/or function of cilium, cytoskeleton, extracellular matrix, WNT signaling, and/or cell migration. Another 20% of the study subjects carried heterozygous URDVs in candidate genes associated with gene transcription regulation, folate metabolism, or glucose metabolism. Presence of URDVs in the candidate genes involving these biological function groups may elevate the risk of developing myelomeningocele in the study cohort.
Highlights
Myelomeningocele (MMC) affects one in 1000 newborns annually worldwide and each surviving child faces tremendous lifetime medical and caregiving burdens
A total of 597,401 high confidence Single nucleotide variants (SNVs) that passed filtering steps described in the Materials and Method section were selected for further analysis
This study revealed that 70% of the 506 MMC subjects consisting of the two ethnic groups with the highest prevalence of myelomeningocele in North America carry ultra-rare deleterious variants (URDVs) in 302 genes previously demonstrated to cause neural tube defect (NTD) phenotypes in animal m odels[9] or associated with human NTDs (Supplementary Table 2)
Summary
Myelomeningocele (MMC) affects one in 1000 newborns annually worldwide and each surviving child faces tremendous lifetime medical and caregiving burdens. Half of the study subjects carried heterozygous URDVs in multiple genes involved in the structure and/or function of cilium, cytoskeleton, extracellular matrix, WNT signaling, and/or cell migration. NE cells at the midline and the dorsolateral regions form the medial hinge point (MHP) and the dorsolateral hinge point (DLHP) through mechanisms including apical construction and localized cell proliferation, and proliferation of non-neural ectodermal cells (NNE) that facilitate closing of the neural tube[1] (Fig. 1) These biological processes involve sensing signals in the extracellular matrix by signal receptors on the cell surface and sub-organelles (e.g. mechanochemical sensors on primary cilia) which subsequently trigger remodeling of cytoskeletal structures and orchestrate directional migration of NE and NNE c ells[2]. The potential contribution of the observed results to MMC development in humans will be discussed
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