Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CIBERER, Murcia, Spain.
Sección de Genética Médica y Dismorfología, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain.
Pediatr Res. 2018 Jan;83(1-1):119-127. doi: 10.1038/pr.2017.201. Epub 2017 Sep 20.
BackgroundFetal 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.MethodsA 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.ResultsRare (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.ConclusionsOur 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.
胎儿酒精综合征（FAS）是由母体在怀孕期间饮酒引起的；尽管可能涉及其他因素，但由于发育和严重程度与酒精摄入量没有直接关系，因此可能与先天性糖基化障碍（CDG）的临床表现相似，酒精引起的异常糖基化在 FAS 中起作用。因此，导致 CDG 的基因突变，影响糖基化相关基因，也可能与 FAS 有关。
对 25 名有产前酒精暴露史的 FAS 患者和 20 名对照进行了涉及 N-糖基化的 74 个基因的panel 测序。通过 HPLC 评估转铁蛋白糖型。
FAS 患者比对照组更常出现罕见（次要等位基因频率<0.009）错义/剪接位点变异（84% vs. 50%；P=0.034，优势比：5.25，95%置信区间：1.3-20.9）。值得注意的是，有 3 名患者，但没有对照，携带了在 CDG 患者中发现的具有功能影响的变异。此外，具有最严重临床表型的患者是唯一携带两种具有功能影响的变异的患者。家族研究支持遗传缺陷与妊娠期间饮酒的结合可能在 FAS 发展中起作用。
我们的研究支持涉及 N-糖基化的基因的罕见变异可能在产前酒精暴露下 FAS 的发展和严重程度中起作用。
