Introduction

Congenital disorders of glycosylation (CDG) are inborn errors of glycan metabolism with high clinical variability. Only a few antenatal cases have been described with CDG. Due to a lack of reliable biomarker, prenatal CDG diagnostics relies primarily on molecular studies. In the presence of variants of uncertain significance prenatal glycosylation studies are very challenging.

Case report

A consanguineous couple had a history of second-trimester fetal demise with tetralogy of Fallot and skeletal dysplasia. In the consecutive pregnancy, the second trimester ultrasonography showed skeletal dysplasia, vermian hypoplasia, congenital heart defects, omphalocele and dysmorphic features. Prenatal chromosomal microarray revealed a large region of loss of heterozygosity. Demise occurred at 30 weeks. Fetal whole exome sequencing showed a novel homozygous likely pathogenic variant in ALG3 and a variant of uncertain significance in COG5.

Methods

Western blot was used to quantify ALG3, COG5, COG6, and the glycosylation markers ICAM-1 and LAMP2. RT-qPCR was used for ALG3 and COG5 expression in cultured amniocytes and compared to age matched controls.

Results

ALG3 and COG5 mRNA levels were normal. ICAM-1, LAMP2, ALG3 and COG5 levels were decreased in cultured amniocytes, suggesting the possible involvement of both genes in the complex phenotype.

Conclusion

This is the first case of successful use of glycosylated biomarkers in amniocytes, providing further options of functional antenatal testing in CDG.

中文翻译：

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通过羊膜穿刺术检测到由于ALG3和COG5变异引起的胎儿糖基化缺陷：具有胚胎致死表型的复杂糖基化缺陷

介绍

先天性糖基化疾病（CDG）是先天性糖代谢异常，具有很高的临床变异性。CDG仅描述了少数产前病例。由于缺乏可靠的生物标志物，产前CDG诊断主要依靠分子研究。在存在不确定性显着的变体的情况下，产前糖基化研究非常具有挑战性。

案例报告

一对近亲夫妇有妊娠中期胎儿死亡的历史，伴有法洛氏四联症和骨骼发育不良。在连续妊娠中，妊娠中期超声检查显示骨骼发育异常，Vermian发育不全，先天性心脏缺陷，食管膨出和畸形。产前染色体微阵列显示大面积杂合性缺失。消亡发生在30周。胎儿全外显子测序显示ALG3中有一个新的纯合子致病变异，而COG5中有不确定意义的变异。

方法

Western印迹用于定量ALG3，COG5，COG6以及糖基化标记ICAM-1和LAMP2。RT-qPCR用于培养的羊膜细胞中ALG3和COG5的表达，并与年龄匹配的对照进行比较。

结果

ALG3和COG5 mRNA水平正常。培养的羊膜细胞中ICAM-1，LAMP2，ALG3和COG5水平降低，表明这两个基因可能参与了复杂的表型。

结论

这是成功地在羊膜细胞中使用糖基化生物标志物的第一个案例，为CDG中的功能性产前检查提供了更多选择。