Genetic association of the glycine cleavage system genes and myelomeningocele.
BACKGROUND
Neural tube defects (NTDs) are one of the most common congenital birth defects, with myelomeningocele (MM) being the most severe form compatible with life. Recent studies show a link between mitochondrial folate one carbon metabolism and NTDs by means of the glycine cleavage system (GCS). We hypothesize that single nucleotide polymorphisms and novel variants in the coding regions of the GCS genes increase the risk for MM.


METHODS
DNA was obtained from 96 subjects with MM born before the United States mandated folic acid fortification of grains in 1998. Primers were designed for polymerase chain reaction amplification and sequencing of all exons in the AMT gene, one of four genes in the GCS, followed by identification of single nucleotide polymorphisms and novel variants. An additional 252 MM subjects underwent whole exome sequencing to examine all four GCS genes (aminomethyltransferase, glycine dehydrogenase, glycine cleavage system protein-H, and dihydrolipoamide dehydrogenase).


RESULTS
We identified six novel, heterozygous variants in the AMT gene with three predicted to be deleterious to AMT function (p.Val7Leu, p.Pro251Arg, and p.Val380Met). Five extremely rare, known heterozygous variants were found in the AMT gene and one in the GLDC gene. No novel variants in the exons of the other two GCS genes (DLD and GCSH) were identified.


CONCLUSIONS
We identified novel and rare, known variants in two of the four GCS genes that may contribute to the development of MM. Consistent with previous findings, the current study provides additional support that genetic variations in GCS genes contribute to the risk of NTDs. Birth Defects Research (Part A) 106:847-853, 2016. © 2016 Wiley Periodicals, Inc.
Division of Neonatology, Department of Pediatrics, The University of Texas Health Science Center at Houston - McGovern Medical School, Houston, Texas.
Rita H
http://orcid.org/0000-0001-6688-4185
RH
Shah
Division of Medical Genetics, Department of Pediatrics, The University of Texas Health Science Center at Houston - McGovern Medical School, Houston, Texas.
Hope
H
Northrup
Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas Health Science Center at Houston - School of Public Health, Houston, Texas.
James E
JE
Hixson
Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas Health Science Center at Houston - School of Public Health, Houston, Texas.
Alanna C
AC
Morrison
Division of Medical Genetics, Department of Pediatrics, The University of Texas Health Science Center at Houston - McGovern Medical School, Houston, Texas. Kit-Sing.Au@uth.tmc.edu.
Kit Sing
KS
Au
D005260:Female; D056726:Genetic Association Studies; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008591:Meningomyelocele / Q000235:genetics / Q000378:metabolism
D005998:Glycine
aminomethyltransferase; folate metabolism; glycine cleavage system; myelomeningocele