The role of epigenetics in inborn errors of metabolism (IEMs) is poorly investigated. Epigenetic changes can contribute to clinical heterogeneity of affected patients but could also be underestimated determining factors in the occurrence of IEMs. An epigenetic cause of IEMs has been recently described for the autosomal recessive methylmalonic aciduria and homocystinuria, cblC type (cblC disease), and it has been named epi-cblC. Epi-cblC has been reported in association with compound heterozygosity for a genetic variant and an epimutation at the MMACHC locus, which is secondary to a splicing variant (c.515-1G > T or c.515-2A > T) at the adjacent PRDX1 gene. Both these variants cause aberrant antisense transcription and cis-hypermethylation of the MMACHC gene promotor with subsequent silencing. Until now, only nine epi-cblC patients have been reported. We report clinical/biochemical assessment, MMACHC/PRDX1 gene sequencing and genome-wide DNA methylation profiling in 11 cblC patients who had an inconclusive MMACHC gene testing. We also compare clinical phenotype of epi-cblC patients with that of canonical cblC patients. All patients turned out to have the epi-cblC disease. One patient had a bi-allelic MMACHC epimutation due to the homozygous PRDX1:c.515-1G > T variant transmitted by both parents. We found that the bi-allelic epimutation produces the complete silencing of MMACHC in the patient’s fibroblasts. The remaining ten patients had a mono-allelic MMACHC epimutation, due to the heterozygous PRDX1:c.515-1G > T, in association with a mono-allelic MMACHC genetic variant. Epi-cblC disease has accounted for about 13% of cblC cases diagnosed by newborn screening in the Tuscany and Umbria regions since November 2001. Comparative analysis showed that clinical phenotype of epi-cblC patients is similar to that of canonical cblC patients. We provide evidence that epi-cblC is an underestimated cause of inborn errors of cobalamin metabolism and describe the first instance of epi-cblC due to a bi-allelic MMACHC epimutation. MMACHC epimutation/PRDX1 mutation analyses should be part of routine genetic testing for all patients presenting with a metabolic phenotype that combines methylmalonic aciduria and homocystinuria.

中文翻译：

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PRDX1基因相关的epi-cblC疾病是一种常见的先天性钴胺素代谢错误，具有单等位基因或双等位基因MMACHC表观突变

表观遗传学在先天性代谢错误 (IEM) 中的作用研究很少。表观遗传变化可能导致受影响患者的临床异质性，但也可能被低估了 IEM 发生的决定因素。IEMs 的表观遗传原因最近被描述为常染色体隐性甲基丙二酸尿症和高胱氨酸尿症，cblC 型（cblC 病），并被命名为 epi-cblC。据报道，Epi-cblC 与遗传变异的复合杂合性和 MMACHC 基因座处的表观突变相关，后者继发于相邻的剪接变体（c.515-1G > T 或 c.515-2A > T） PRDX1 基因。这两种变体都会导致 MMACHC 基因启动子的异常反义转录和顺式高甲基化以及随后的沉默。到目前为止，仅报告了 9 例 epi-cblC 患者。我们报告了 11 名 MMACHC 基因检测结果不确定的 cblC 患者的临床/生化评估、MMACHC/PRDX1 基因测序和全基因组 DNA 甲基化分析。我们还将 Epi-cblC 患者的临床表型与典型 cblC 患者的临床表型进行比较。结果所有患者都患有epi-cblC疾病。由于父母双方传播的纯合 PRDX1:c.515-1G > T 变体，一名患者具有双等位基因 MMACHC 表观突变。我们发现双等位基因表观突变使患者成纤维细胞中的 MMACHC 完全沉默。由于杂合 PRDX1:c.515-1G > T 与单等位基因 MMACHC 遗传变异相关，其余 10 名患者具有单等位基因 MMACHC 表观突变。自 2001 年 11 月以来，在托斯卡纳和翁布里亚地区通过新生儿筛查诊断的 cblC 病例中，Epi-cblC 疾病约占 13%。比较分析表明，epi-cblC 患者的临床表型与典型 cblC 患者相似。我们提供的证据表明，epi-cblC 是钴胺素代谢先天性错误的一个被低估的原因，并描述了由于双等位基因 MMACHC 表观突变而导致的第一例 epi-cblC。MMACHC 表观突变/PRDX1 突变分析应成为所有具有甲基丙二酸尿症和高胱氨酸尿症的代谢表型的患者常规基因检测的一部分。我们提供的证据表明，epi-cblC 是钴胺素代谢先天性错误的一个被低估的原因，并描述了由于双等位基因 MMACHC 表观突变而导致的第一例 epi-cblC。MMACHC 表观突变/PRDX1 突变分析应成为所有具有甲基丙二酸尿症和高胱氨酸尿症的代谢表型的患者常规基因检测的一部分。我们提供的证据表明，epi-cblC 是钴胺素代谢先天性错误的一个被低估的原因，并描述了由于双等位基因 MMACHC 表观突变而导致的第一例 epi-cblC。MMACHC 表观突变/PRDX1 突变分析应成为所有具有甲基丙二酸尿症和高胱氨酸尿症的代谢表型的患者常规基因检测的一部分。