Background

ALG12-CDG is a rare autosomal recessive type I congenital disorder of glycosylation (CDG) due to pathogenic variants in ALG12 which encodes the dolichyl-P-mannose:Man-7-GlcNAc-2-PP-dolichyl-alpha-6-mannosyltransferase. Thirteen patients from unrelated 11 families have been reported, most of them result in broad multisystem manifestations with clinical variability. It is important to validate abnormal glycosylation to establish causal relationship.

Case report

Here, we report two siblings with novel compound heterozygous variants in ALG12: c.443T>C, p.(Leu148Pro) and c.412_413insCGT, p.(Gln137_Phe138insSer). Both patients showed global developmental delay, microcephaly, hypotonia, failure to thrive, facial dysmorphism, skeletal malformations and coagulation abnormalities, which are common in ALG12-CDG. In addition, one of our patients showed left hydronephrosis, which is a novel clinical feature in ALG12-CDG. Brain MRI showed hypoplasia of cerebrum, brain stem and cerebellar vermis in both patients. N-glycosylation defects of trypsin digested transferrin peptides were revealed by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), and electrospray ionization MS verified the lack of N-glycans in transferrin.

Conclusions

The present study can add hydronephrosis to phenotypic spectrum of ALG12-CDG. Since the symptoms of ALG12-CDG are quite diverse, the combination of whole-exome sequencing and transferrin glycopeptide analysis with MS, can help diagnosis of ALG12-CDG.

中文翻译：

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N-糖基化受损兄弟姐妹的新型 ALG12 变异和肾积水

背景

ALG12-CDG 是一种罕见的常染色体隐性遗传的 I 型先天性糖基化疾病 (CDG)，原因是ALG12中的致病性变异编码多利奇基-P-甘露糖：Man-7-GlcNAc-2-PP-dolichyl-alpha-6-mannosyltransferase。已经报道了来自不相关的 11 个家庭的 13 名患者，其中大多数导致具有临床变异性的广泛的多系统表现。验证异常糖基化以建立因果关系非常重要。

案例报告

在这里，我们报告了在ALG12中具有新型复合杂合变体的两个兄弟姐妹：c.443T>C, p.(Leu148Pro) 和 c.412_413insCGT, p.(Gln137_Phe138insSer)。两名患者均表现出整体发育迟缓、小头畸形、肌张力减退、发育迟缓、面部畸形、骨骼畸形和凝血异常，这些在 ALG12-CDG 中很常见。此外，我们的一名患者出现左侧肾积水，这是 ALG12-CDG 的新临床特征。脑部MRI显示两名患者大脑、脑干和小脑蚓部发育不全。基质辅助激光解吸/电离质谱（MALDI-MS）揭示了胰蛋白酶消化转铁蛋白肽的N-糖基化缺陷，电喷雾电离MS证实了N缺乏-转铁蛋白中的聚糖。

结论

本研究可以将肾积水添加到 ALG12-CDG 的表型谱中。由于 ALG12-CDG 的症状较为多样，因此将全外显子组测序和转铁蛋白糖肽分析与 MS 相结合，有助于 ALG12-CDG 的诊断。