Abstract
Background
Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption during pregnancy; although additional factors might be involved, as development and severity are not directly related to alcohol intake. The abnormal glycosylation caused by alcohol might play a role in FAS according to the clinical similarities shared with congenital disorders of glycosylation (CDG). Thus, mutations underlying CDG, affecting genes involved in glycosylation, could also be involved in FAS.
Methods
A panel of 74 genes involved in N-glycosylation was sequenced in 25 FAS patients and 20 controls with prenatal alcohol exposure. Transferrin glycoforms were evaluated by HPLC.
Results
Rare (minor allele frequency<0.009) missense/splice site variants were more frequent in FAS than controls (84% vs. 50%; P=0.034, odds ratio: 5.25, 95% confidence interval: 1.3–20.9). Remarkably, three patients, but no controls, carried variants with functional effects identified in CDG patients. Moreover, the patient with the most severe clinical phenotype was the only one carrying two variants with functional effects. Family studies support that the combination of a genetic defect and alcohol consumption during pregnancy might have a role in FAS development.
Conclusions
Our study supports that the rare variants of genes involved in N-glycosylation could play a role in the development and severity of FAS under prenatal alcohol exposure.
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Acknowledgements
We acknowledge Irene Martínez-Martínez and Salvador Espín for their assistance on HPLC analysis.
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AUTHOR CONTRIBUTIONS
M.E.M.-B., J.C., E.G.-N., and V.V. designed research, analyzed the data, and wrote the paper. M.J.B.-M., V.L.-G., L.M.-R., O.G.-A., M.D.C., and E.G.-N. collected patients and clinical data and revised the paper. R.L.-G., M.E.M.-B., and A.M. performed biochemical and genetics experiments. A.I.M. and J.P. performed NGS analysis and genetic analysis.
STATEMENT OF FINANCIAL SUPPORT
MEM-B holds a postdoctoral fellowship from Fundacion Espanola de Trombosis y Hemostasia, Spain. This work was supported by PI15/00079 and CB15/00055 from ISCIII & FEDER; 19873/GERM/15 Fundacion Seneca.
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de la Morena-Barrio, M., Ballesta-Martínez, M., López-Gálvez, R. et al. Genetic predisposition to fetal alcohol syndrome: association with congenital disorders of N-glycosylation. Pediatr Res 83, 119–127 (2018). https://doi.org/10.1038/pr.2017.201
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DOI: https://doi.org/10.1038/pr.2017.201
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