Genetic variant analysis and prenatal diagnosis for Chinese pedigrees affected with cblC methylmalonic acidemia

Abstract

To detect variants of the MMACHC gene among 110 ethnic Han Chinese pedigrees affected with metabolic deficiency methylmalonic acidemia (MMA) of cobalamin C (cblC). Peripheral blood samples were collected from the probands and their parents. Following DNA extraction, the coding regions of the MMACHC gene were subjected to PCR amplification, Sanger sequencing and quantitative PCR assaying. For 48 pedigrees, chorionic villus samples were taken for prenatal genetic diagnosis. Thirty five types of variants were detected among the 110 pedigrees, which included missense, nonsense, frameshifting, splicing variants and exonic deletions. Most variants have occurred in exons 4 (73.18%). The detection rate for c.609G>A (p.Trp203Ter) variant was the highest (33.64%), followed by c.658_660delAAG (12.27%), c.567dupT (9.09%) and c.80A>G (6.82%). Two variants, namely c.57_58insT (p.Gly20Trpfs*14) and c.505_506delAT (p.Ile169Argfs*12), were unreported previously and both were of frameshifting types. For the 48 pedigrees undergoing prenatal diagnosis, 14 fetuses were found to be normal, 24 have carried heterozygous variants, the remaining 10 have carried compound heterozygous or homozygous variants. The discovery of the two novel variants has expanded the spectrum of the MMACHC gene variants among ethnic Han population. Above finding has provide a basis for the prenatal diagnosis and genetic counseling for the affected pedigrees.