Identification of novel candidate risk genes for myelomeningocele within the glucose homeostasis/oxidative stress and folate/one‐carbon metabolism networks

Hillman, Paul; Baker, Craig; Hebert, Luke; Brown, M. R. W.; Hixson, James E.; Ashley–Koch, Allison; Morrison, Alanna C.; Au, Kit Sing

doi:10.1002/mgg3.1495

Cited by 7 publications

(8 citation statements)

References 44 publications

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“…Of 364 subjects in the study cohort who bore at least one URDV in an NTD candidate gene, nearly 75% had URDVs affecting genes associated with cilium, WNT signaling, ECM, cytoskeleton and cell migration remodeling suggesting they may confer increased genetic risk to MMC development. The remaining 25% of MMC subjects had URDV-containing NTD candidate genes that were associated with other gene functions such as transcription modulation, folate one carbon metabolism network and glucose oxidative stress 21 not related to the ontologies examined in this study.…”

Section: And Supplementarymentioning

confidence: 88%

“…For sequence data that passed variant level and sample level quality filters, variant calling was conducted using Genome Analysis Toolkit GATK HaplotypeCaller version 3.x following best practice guidelines 55 . Additional variant filtering steps had been described previously 21,40 . Briefly, only variants designated a "PASS" by Variant Quality Score Recalibration (VQSR), met map quality score < 20, and having inbreeding coefficient < -0.3 were retained for further analysis.…”

Section: Discussionmentioning

confidence: 99%

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Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration

Au¹,

Hebert²,

Hillman³

et al. 2021

Sci Rep

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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.

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Section: And Supplementarymentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration

Au¹,

Hebert²,

Hillman³

et al. 2021

Sci Rep

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“…Several gene mutations have been associated with myelomeningocele. Hilman etal identified novel candidate risk gene in patients of myelomeningocele within glucose homeostasis / oxidative stress and folate/ one carbon metabolism networks 26 . Lei etal studied the CELSR1 coding region sequence among patients of spina bifida and found a novel mutation in CELSR1 gene in patients of Spina Bifida 27 .…”

Section: Discussionmentioning

confidence: 99%

Detection of Novel mutation in VANGL1 gene indicating genetic association of Myelomeningocele

Fatima¹,

Iftikhar²,

Gul³

et al. 2021

PJMHS

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Aim: To detect the novel mutation in VANGL1 gene indicating genetic association of Myelomeningocele. Methodology: The study design was cross sectional. It comprises of sixty individuals, of them fifty were diagnosed cases of myelomeningocele and ten were healthy individuals taken as controls. The cases were collected from Jinnah Postgraduate Medical Center. The study was carried out in Dow Diagnostic and Research Laboratory (D.D.R.L.). Most of the patients were less than one year of age. The cases were evaluated for various other parameters like site and size of cyst and associated features like presence of hydrocephalus in the individuals. Since folic acid deficiency is the key component in the causation of the disease so mothers were also asked about the consumption of folic acid. Blood was drawn from patients after a written permission from the parents of the concerned patient. It was followed by the conduction of PCR to seek for any mutation in VANGL1 gene. Results: We found a rare mutation in VANGL1 gene revealing substitution of valine to serine at position 239 i.e. V239S. Hydrocephalus being the associated anomaly was present in 32% of the patients. Most of the affected individuals were males. 98% mothers of the sufferers did not take folic acid during pregnancy. In most of the patients, lump was present on the lumbar region. Conclusion: Myelomeningocele is a congenital birth defect with lifelong complications. Its prevalence can be decreased by taking certain measures. Periconceptional intake of folic acid has been established to lessen the risk of the disease. We identified a rare mutation in VANGL1 gene that may result in the causation of myelomeningocele. Keywords: Neural tube defects, mutation, myelomeningocele.

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“…A more recent strategy toward defining genetic contributions to NTD risk has employed whole exome sequencing (WES) for searches of protein coding regions of candidate genes or pathways coupled with gene collapsing strategies to detect putative NTD risk genes and variants. Examples include studies that examined 511 NTD cases for exon variants in glucose homeostasis/oxidative stress and OCM network (Hillman et al, 2020) or WNT signaling pathway genes (Hebert et al, 2020). Another study looked at the association between rare variants in specific functional pathways and in multiple subphenotypes of human neural tube defects (Zou et al, 2020).…”

Section: These Investigators Usedmentioning

confidence: 99%

Unraveling the complex genetics of neural tube defects: From biological models to human genomics and back

Wolujewicz

Steele

Kaltschmidt

et al. 2021

Genesis

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Neural tube defects (NTDs) are a classic example of preventable birth defects for which there is a proven‐effective intervention, folic acid (FA); however, further methods of prevention remain unrealized. In the decades following implementation of FA nutritional fortification programs throughout at least 87 nations, it has become apparent that not all NTDs can be prevented by FA. In the United States, FA fortification only reduced NTD rates by 28–35% (Williams et al., 2015). As such, it is imperative that further work is performed to understand the risk factors associated with NTDs and their underlying mechanisms so that alternative prevention strategies can be developed. However, this is complicated by the sheer number of genes associated with neural tube development, the heterogeneity of observable phenotypes in human cases, the rareness of the disease, and the myriad of environmental factors associated with NTD risk. Given the complex genetic architecture underlying NTD pathology and the way in which that architecture interacts dynamically with environmental factors, further prevention initiatives will undoubtedly require precision medicine strategies that utilize the power of human genomics and modern tools for assessing genetic risk factors. Herein, we review recent advances in genomic strategies for discovering genetic variants associated with these defects, and new ways in which biological models, such as mice and cell culture‐derived organoids, are leveraged to assess mechanistic functionality, the way these variants interact with other genetic or environmental factors, and their ultimate contribution to human NTD risk.

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Identification of novel candidate risk genes for myelomeningocele within the glucose homeostasis/oxidative stress and folate/one‐carbon metabolism networks

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 7 publications

References 44 publications

Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration

Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration

Detection of Novel mutation in VANGL1 gene indicating genetic association of Myelomeningocele

Unraveling the complex genetics of neural tube defects: From biological models to human genomics and back

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