First pathogenic non-coding variant in MMACHC: a functional deletion in the 5'-UTR associated with cobalamin C deficiency.

BACKGROUND: Methylmalonic acidemia, also known as methylmalonic aciduria, is a congenital organic acidemia. The accumulation of methylmalonic acid and its bypass metabolites can cause multi-system damage, particularly central nervous system damage. METHODS: We present a case of methylmalonic acidemia in a Chinese Han female child with the MMACHC gene variants. Whole exome sequencing and bioinformatics analysis were performed on the proband. Sanger sequencing, breakpoint PCR amplification, and qPCR gene expression verification were conducted on family members. RESULTS: The proband exhibited feeding difficulties, developmental delay and epilepsy. Clinical findings and laboratory tests were consistent with methylmalonic acidemia. Conventional genetic testing solely identified a heterozygous variant c.658-660delAAG (p.Lys220del) of the MMACHC gene inherited from the father. Since the single allele variation did not match the recessive inheritance pattern of the disease, bioinformatics analysis uncovered a 1.072 kb heterozygous deletion in the 5’-UTR region of the MMACHC gene inherited from the mother. PCR and Sanger sequencing confirmed the variant site, and qPCR verified the diminished gene expression within the deletion region. CONCLUSIONS: This study reports the first instance of abnormal cobalamin metabolism due to the deletion of the 5’-UTR region of the MMACHC gene which expands the spectrum of gene variations. This study reveals a new diagnosis approach of methylmalonic acidemia, especially the variant located in the UTR region of the gene. We recommend that in patients with typical disease manifestations, although there is a single heterozygous gene variant, we should actively search for the exact variant site.