Genetic variations in the GLUT3 gene associated with myelomeningocele

Abstract

Objective Our objectives are to examine the extent of described sequence variation in the glucose transporter 3 (GLUT3) gene in myelomeningocele (MM) children, identify novel variations in the GLUT3 gene in these children and determine whether these variations may confer risk of MM. Study Design We sequenced the 10 exons of GLUT3, including exon-intron boundaries, on 96 children with MM. Sequencing was performed with Sanger methods and results analyzed with DNA analysis software. Frequencies of known single nucleotide polymorphisms (SNPs) were identified, those differing from the reference sequence (GRCh37/hg19 assembly) were considered variations. Results Six novel and nine previously described, genetic variations were identified in our population. The novel variations include a large, 83 base pair deletion involving the core promoter region and part of Exon 1 (1/96 children), and a two base pair deletion in the coding sequence of Exon 4 (1/96 children). The remaining novel variations are located in the introns in the proximity of the splice sites. Novel mutations in GLUT3 were observed among 6.25% of our population. Additionally, the frequency of the rare allele for rs17847972 located in a splice donor site is higher (P<0.001) in MM in our population than expected. Conclusion We identified previously undescribed deletions and single nucleotide variations involving the GLUT3 gene that may be associated with increased susceptibility to MM. Of particular interest, the two deletions involve both an important core promoter site and a coding region predicted to have deleterious effect. The functional significance of these findings is under investigation.

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

“…Kibar etal identified five novel missense variants in VANGL1, pSer83Leu, p.Phe153Ser, p. Arg181Gln, p.Leu202Phe and p.Ala404Ser occuring in sporadic and familial cases of spinal dysraphisms 29 . Connealy etal established the genetic variation in GLUT3 gene in patients of myelomeningocele 30 . Merello etal found identified three heterozygous missense variants in VANGL1, p.Ala187Val, p.Asp389His, and p.Arg517His in individuals suffering from neural tube defects 31 .…”

Identifying biomarkers for prenatal diagnosis of neural tube defects based on “omics”

“…Copy number variants have also been found in NTDs through array-based comparative genomic hybridization and single-nucleotide polymorphism (SNP) analysis. 51,52 Guan et al determined that the SNPs of ITPK1 in maternal blood might be associated with spina bifida. 53 A large-scale next-generation sequencing (NGS) analysis of a cohort of 52 patients used a candidate gene panel approach, in addition to identifying variants in known genes of the planar cell polarity pathway; variants in new genes such as DISP1 and FREM2 were also revealed.…”

Finding the genetic mechanisms of folate deficiency and neural tube defects—Leaving no stone unturned

“…Many recent studies have implicated rare genetic variants as contributing major effects in common complex diseases (Cirulli & Goldstein, ). Indeed, approaches used to scan through sequences of candidate genes in exomes of affected subjects have identified rare deleterious genetic variants potentially contributing to some human NTDs (Connealy, Northrup, & Au, ; De Marco et al, ; Lemay et al, ; Ruggiero, Northrup, & Au, ; Wang, De Marco, et al, ). The impact of the FA fortification mandate on the penetrance of variants in genes rescuable by FA should be carefully weighed when designing studies to identify these variants.…”