Molecular and Cell Biology Laboratory of Neurometabolic Diseases, Paediatric Neurology Unit and Laboratories, Meyer Children's Hospital, Viale Pieraccini 24, 50139, Florence, Italy.
INSERM, UMR_S1256 Nutrition-Genetics-Environmental Risk Exposure and Reference Centre of Inborn Metabolism Diseases, University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy), Nancy, France.
Clin Epigenetics. 2021 Jul 2;13(1):137. doi: 10.1186/s13148-021-01117-2.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
背景：表观遗传学在先天性代谢缺陷（IEM）中的作用尚未得到充分研究。表观遗传变化可能导致受影响患者的临床异质性，但也可能被低估为 IEM 发生的决定因素。最近，一种常染色体隐性甲基丙二酸血症和同型胱氨酸尿症 cblC 型（cblC 病）的表观遗传病因已被描述，并被命名为 epi-cblC。epi-cblC 与 MMACHC 基因座的遗传变异和表观遗传突变的复合杂合性有关，这是由于相邻 PRDX1 基因的剪接变异（c.515-1G> T 或 c.515-2A> T）引起的。这两种变异都会导致 MMACHC 基因启动子的异常反义转录和顺式高甲基化，从而导致沉默。到目前为止，仅报道了 9 例 epi-cblC 患者。
方法：我们报告了 11 例 cblC 患者的临床/生化评估、MMACHC/PRDX1 基因测序和全基因组 DNA 甲基化谱分析，这些患者的 MMACHC 基因检测结果不确定。我们还比较了 epi-cblC 患者和经典 cblC 患者的临床表型。
结果：所有患者均被诊断为 epi-cblC 疾病。一名患者因父母双方均携带 PRDX1:c.515-1G>T 变异而具有双等位基因 MMACHC 表观遗传突变。我们发现，双等位基因的表观遗传突变导致患者成纤维细胞中 MMACHC 的完全沉默。其余 10 名患者的 MMACHC 基因存在单等位基因表观遗传突变，原因是杂合 PRDX1:c.515-1G>T，与单等位基因 MMACHC 遗传变异有关。自 2001 年 11 月以来，epi-cblC 疾病约占托斯卡纳和翁布里亚地区通过新生儿筛查诊断的 cblC 病例的 13%。比较分析表明，epi-cblC 患者的临床表型与经典 cblC 患者相似。
结论：我们提供了证据表明 epi-cblC 是一种被低估的钴胺素代谢先天性缺陷的原因，并描述了首例由双等位基因 MMACHC 表观遗传突变引起的 epi-cblC。所有表现出甲基丙二酸血症和同型胱氨酸尿症混合代谢表型的患者，都应进行 MMACHC 表观遗传突变/PRDX1 突变分析，作为常规基因检测的一部分。
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