Mutation spectrum and genotype-phenotype correlation of pediatric patients with methylmalonic acidemia

Background: MMA incidence is significantly greater in China than in the rest of the world, but the mutation spectrum of MMA in China has not yet been mapped.

Methods: We summarized published MMA-related articles and conducted a systematic meta-analysis of the literature.

Results: We analyzed the gene variants information of 926 pediatric MMA patients in China; 517 were children with combined MMA, and 409 were children with isolated MMA. Almost all combined MMA cases were caused by MMACHC gene mutations (cblC-type). The c.609G>A variation was the most common in cblC-type children, accounting for 43.01%, followed by c.658_660delAAG, c.482G>A, c.80A>G, and c.394C>T variations. Mut-type MMA patients accounted for 98.8% (404/409) of all isolated MMA cases. The variant MMUT c.729_730insTT accounted for 10.30% (80/802) of all variants and was the most common variant in mut-type children, followed by c.323G>A and c.1106G>A.

Conclusions: Our study summarized and characterized the mutation spectrum of Chinese pediatric patients with MMACHC and MMUT variants, and we also analyzed the relationships between common variants, onset time, and clinical phenotype. These findings will contribute to understanding the phenotypic characteristics and overall pathogenesis of MMA patients, supporting the goal of gene therapy.

Impact: The incidence of methylmalonic academia (MMA) in China is significantly greater than that in the rest of the world, but the mutation spectrum of MMA in China has not yet been mapped. In this paper, for the first time, we investigated hot-spot gene variants in MMA patients in China and comprehensively described the MMA gene mutation spectrum of the Chinese population. We explored the relationship between MMA genotype and clinical phenotype in patients, providing a basis for family genetic counseling, prenatal diagnosis, and newborn screening.