The search for genetic determinants of human neural tube defects.

PURPOSE OF REVIEW An update is presented regarding neural tube defects (NTDs) including spina bifida and anencephaly, which are among the most common serious birth defects world-wide. Decades of research suggest that no single factor is responsible for neurulation failure, but rather NTDs arise from a complex interplay of disrupted gene regulatory networks, environmental influences and epigenetic regulation. A comprehensive understanding of these dynamics is critical to advance NTD research and prevention. RECENT FINDINGS Next-generation sequencing has ushered in a new era of genomic insight toward NTD pathophysiology, implicating novel gene associations with human NTD risk. Ongoing research is moving from a candidate gene approach toward genome-wide, systems-based investigations that are starting to uncover genetic and epigenetic complexities that underlie NTD manifestation. SUMMARY Neural tube closure is critical for the formation of the human brain and spinal cord. Broader, more all-inclusive perspectives are emerging to identify the genetic determinants of human NTDs.

[1]  Y. Kamatani,et al.  Comprehensive evaluation of structural variation detection algorithms for whole genome sequencing , 2019, Genome Biology.

[2]  Jianxin Wu,et al.  Abnormal level of CUL4B-mediated histone H2A ubiquitination causes disruptive HOX gene expression , 2019, Epigenetics & Chromatin.

[3]  A. Strasser,et al.  Loss of p53 Causes Stochastic Aberrant X-Chromosome Inactivation and Female-Specific Neural Tube Defects. , 2019, Cell reports.

[4]  Wei Liu,et al.  Association of neural tube defects with maternal alterations and genetic polymorphisms in one-carbon metabolic pathway , 2019, Italian Journal of Pediatrics.

[5]  W. Carré,et al.  Targeted panel sequencing establishes the implication of planar cell polarity pathway and involves new candidate genes in neural tube defect disorders , 2019, Human Genetics.

[6]  Yi Guo,et al.  TRIM4 is associated with neural tube defects based on genome-wide DNA methylation analysis , 2019, Clinical epigenetics.

[7]  G. Shaw,et al.  Variants identified in PTK7 associated with neural tube defects , 2019, Molecular genetics & genomic medicine.

[8]  G. Rouleau,et al.  Whole exome sequencing identifies novel predisposing genes in neural tube defects , 2018, Molecular genetics & genomic medicine.

[9]  M. Ross,et al.  Dominant negative GPR161 rare variants are risk factors of human spina bifida , 2018, Human molecular genetics.

[10]  J. Huo,et al.  Elevated H3K79 homocysteinylation causes abnormal gene expression during neural development and subsequent neural tube defects , 2018, Nature Communications.

[11]  M. Ross,et al.  Threshold for neural tube defect risk by accumulated singleton loss-of-function variants , 2018, Cell Research.

[12]  Wei Li,et al.  A homozygous mutation p.Arg2167Trp in FREM2 causes isolated cryptophthalmos , 2018, Human molecular genetics.

[13]  Edward R. Smith,et al.  De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus , 2018, Neuron.

[14]  Alexander Hanbo Li,et al.  The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia , 2018, Human molecular genetics.

[15]  L. Davidson,et al.  The non-canonical Wnt-PCP pathway shapes the mouse caudal neural plate , 2018, Development.

[16]  R. Finnell,et al.  Digenic variants of planar cell polarity genes in human neural tube defect patients. , 2018, Molecular genetics and metabolism.

[17]  S. Mundlos,et al.  Structural variation in the 3D genome , 2018, Nature Reviews Genetics.

[18]  B. Wlodarczyk,et al.  Formate rescues neural tube defects caused by mutations in Slc25a32 , 2018, Proceedings of the National Academy of Sciences.

[19]  J. Eisfeldt,et al.  Targeted copy number screening highlights an intragenic deletion of WDR63 as the likely cause of human occipital encephalocele and abnormal CNS development in zebrafish , 2018, Human mutation.

[20]  C. Schwartz,et al.  Key apoptotic genes APAF1 and CASP9 implicated in recurrent folate-resistant neural tube defects , 2018, European Journal of Human Genetics.

[21]  Hongyan Wang,et al.  Novel Mutation of LRP6 Identified in Chinese Han Population Links Canonical WNT Signaling to Neural Tube Defects. , 2018, Birth defects research.

[22]  A. Morrison,et al.  Mutations in folate transporter genes and risk for human myelomeningocele , 2017, American journal of medical genetics. Part A.

[23]  H. Northrup,et al.  Finding the genetic mechanisms of folate deficiency and neural tube defects—Leaving no stone unturned , 2017, American journal of medical genetics. Part A.

[24]  Y. Zou,et al.  Sonic Hedgehog switches on Wnt/planar cell polarity signaling in commissural axon growth cones by reducing levels of Shisa2 , 2017, eLife.

[25]  Yukai Du,et al.  Elevated homocysteine levels in mothers with neural tube defects: a systematic review and meta-analysis , 2017, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[26]  R. Lister,et al.  Epigenomic Landscapes of hESC-Derived Neural Rosettes: Modeling Neural Tube Formation and Diseases. , 2017, Cell reports.

[27]  Ana Rolo,et al.  Neural tube closure: cellular, molecular and biomechanical mechanisms , 2017, Development.

[28]  Xin Li,et al.  The impact of structural variation on human gene expression , 2016, Nature Genetics.

[29]  T. Matise,et al.  The orphan GPCR, Gpr161, regulates the retinoic acid and canonical Wnt pathways during neurulation. , 2015, Developmental biology.

[30]  L. Martiniova,et al.  Maternal dietary uridine causes, and deoxyuridine prevents, neural tube closure defects in a mouse model of folate-responsive neural tube defects. , 2015, The American journal of clinical nutrition.

[31]  D. Gallot,et al.  De novo 2q36.1q36.3 interstitial deletion involving the PAX3 and EPHA4 genes in a fetus with spina bifida and cleft palate. , 2014, Birth defects research. Part A, Clinical and molecular teratology.

[32]  Lihua Wu,et al.  Association between PKA gene polymorphism and NTDs in high risk Chinese population in Shanxi. , 2013, International journal of clinical and experimental pathology.

[33]  Lihua Wu,et al.  Association between PTCH1 polymorphisms and risk of neural tube defects in a Chinese population. , 2013, Birth defects research. Part A, Clinical and molecular teratology.

[34]  L. Rangell,et al.  The Ciliary G-Protein-Coupled Receptor Gpr161 Negatively Regulates the Sonic Hedgehog Pathway via cAMP Signaling , 2013, Cell.

[35]  Yiping Shen,et al.  Detection of Copy Number Variants Reveals Association of Cilia Genes with Neural Tube Defects , 2013, PloS one.

[36]  D. Juriloff,et al.  A consideration of the evidence that genetic defects in planar cell polarity contribute to the etiology of human neural tube defects. , 2012, Birth defects research. Part A, Clinical and molecular teratology.

[37]  A. Salic,et al.  Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand. , 2012, Cell reports.

[38]  Y. Zou,et al.  Vangl2 promotes Wnt/planar cell polarity-like signaling by antagonizing Dvl1-mediated feedback inhibition in growth cone guidance. , 2011, Developmental cell.

[39]  M. J. Harris,et al.  An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure. , 2010, Birth defects research. Part A, Clinical and molecular teratology.

[40]  A. Copp,et al.  The relationship between sonic Hedgehog signaling, cilia, and neural tube defects. , 2010, Birth defects research. Part A, Clinical and molecular teratology.

[41]  A. Bassuk,et al.  Genetic basis of neural tube defects. , 2009, Seminars in pediatric neurology.

[42]  A. Wynshaw-Boris,et al.  Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development , 2005, Nature Neuroscience.