{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T03:30:51Z","timestamp":1782790251033,"version":"3.54.5"},"reference-count":19,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T00:00:00Z","timestamp":1620777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Methylmalonic aciduria (MMA) combined with homocystinuria, cobalamin(cbl)C deficiency type (OMIM 277400), is the most common autosomal recessive inherited disorder of intracellular cobalamin metabolism caused by mutations in the <jats:italic>MMACHC<\/jats:italic> gene (OMIM 609831), of which more than 100 mutations have been identified to date. In this study, we only identified a coding mutation in one allele at the <jats:italic>MMACHC<\/jats:italic> gene locus, and no large fragments deletion or duplication were found. Up to now, only three epimutation cblC cases were reported. We hypothesized whether the <jats:italic>MMACHC<\/jats:italic> was hypermethylated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To address this hypothesis, the entire coding region and adjacent splice sites of the panel genes involved in metabolic diseases were sequenced using the Illumina HiSeq X platform, followed by confirmation via Sanger sequencing in their parents and brothers. Methylation analysis of the <jats:italic>MMACHC<\/jats:italic> was performed using an EpiTect Bisulfite Kit and methylation\u2010specific PCR (MSP) to investigate the role of epimutations in cblC disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a clearly pathogenic single heterozygous c.658_660del, p. (K220del) mutation, which was also identified in the mother. Analysis of the <jats:italic>MMACHC<\/jats:italic> indicated a heterozygous epimutation consisting of 34 hypermethylated CpG sites in a CpG island encompassing the promoter and first exon of the <jats:italic>MMACHC<\/jats:italic>, which was also identified in the father. Furthermore, we identified a single heterozygous c.*2C&gt;T mutation in the sixth exon of the <jats:italic>PRDX1<\/jats:italic> (OMIM 176763) in patients and their fathers, which was the only sequence variation that segregated with the <jats:italic>MMACHC<\/jats:italic> methylation. Neither c.658_660del and epimutation in <jats:italic>MMACHC<\/jats:italic> nor c.*2C&gt;T in <jats:italic>PRDX1<\/jats:italic> was discovered in her brother.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We report compound heterozygotes in <jats:italic>MMACHC<\/jats:italic> for a genetic mutation and an epimutation in cblC cases. To our best knowledge, this is the first report of two cblC cases from China caused by compound heterozygous mutations with a coding mutation in one allele and an epimutation in the other at the <jats:italic>MMACHC<\/jats:italic> locus.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1625","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T05:25:36Z","timestamp":1620883536000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Epimutation of <i>MMACHC<\/i> compound to a genetic mutation in cblC cases"],"prefix":"10.1002","volume":"9","author":[{"given":"Xiaoman","family":"Zhang","sequence":"first","affiliation":[{"name":"Henan Key Laboratory of Children\u2019s Genetics and Metabolic Diseases Children's Hospital Affiliated to Zhengzhou University Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology and Genetic Metabolism Children's Hospital Affiliated to Zhengzhou University Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinsen","family":"Song","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Children\u2019s Genetics and Metabolic Diseases Children's Hospital Affiliated to Zhengzhou University Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengbo","family":"Guo","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Children\u2019s Genetics and Metabolic Diseases Children's Hospital Affiliated to Zhengzhou University Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Children\u2019s Genetics and Metabolic Diseases Children's Hospital Affiliated to Zhengzhou University Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuying","family":"Luo","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Children\u2019s Genetics and Metabolic Diseases Children's Hospital Affiliated to Zhengzhou University Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaodong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Children\u2019s Genetics and Metabolic Diseases Children's Hospital Affiliated to Zhengzhou University Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongchen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Children\u2019s Genetics and Metabolic Diseases Children's Hospital Affiliated to Zhengzhou University Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxiao","family":"Li","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Children\u2019s Genetics and Metabolic Diseases Children's Hospital Affiliated to Zhengzhou University Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongxing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology and Genetic Metabolism Children's Hospital Affiliated to Zhengzhou University Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7742-4678","authenticated-orcid":false,"given":"Haiyan","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology and Genetic Metabolism Children's Hospital Affiliated to Zhengzhou University Henan Children's Hospital Zhengzhou Children's Hospital Zhengzhou 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