Mol Genet Metab. 2025 Nov 3;146(4):109280. doi: 10.1016/j.ymgme.2025.109280. Online ahead of print.
ABSTRACT
PURPOSE: The cblG inborn error of vitamin B12 metabolism is associated with pathogenic variants in the MTR gene, which encodes methionine synthase. Approximately 50 patients with the disorder have been reported, and 54 potentially causal MTR variants published.
METHODS: We performed next generation sequencing and copy number variant analysis of MTR on genomic DNA from 29 cblG patients, including 7 patients that had been previously sequenced with incomplete results. All patients had been diagnosed using somatic cell complementation analysis.
RESULTS: We identified two potential causal variants in each of the patients analyzed, although parental phasing was not done. 39 different variants were identified, including 24 not previously described in the published literature. The most common identified causal variant was c.3518C > T, p.P1173L (8 alleles). The previously identified deep intronic variants c.340-166 A > T and c.609 + 1088G > A were also seen frequently (6 alleles each). Among the newly identified variants, the most common were c.2020C > T p.Arg674Cys (3 alleles) and c.1325C > A, p.Ala442Glu (2 alleles).
CONCLUSION: Identification of pathogenic or likely pathogenic variants was enhanced by knowledge of complementation status which has become less frequent as somatic cell testing becomes less readily available.
PMID:41202372 | DOI:10.1016/j.ymgme.2025.109280
