[Genetic analysis of newborns with abnormal metabolism of 3-hydroxyisovalerylcarnitine].

OBJECTIVE: To investigate the genetic characterization of 3-hydroxyisovalerylcarnitine (C5-OH) metabolic abnormality in neonates. METHODS: Fifty two newborns with increased C5-OH, C5-OH/C3 and C5-OH/C8 detected by tandem mass spectrometry during neonatal screening were enrolled in the study. Genomic DNA was extracted from the whole blood samples of 52 cases and their parents. Seventy-nine genes associated with genetic and metabolic diseases including MCCC1, MCCC2 were targeted by liquid capture technique. Variation information of these genes was examined by high-throughput sequencing and bioinformatic analysis, and then was classified based on the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. The genetic types were classified as wild-type, MCCC1-maternal-mutation, MCCC1-paternal-mutation and MCCC2-mutation. Wilcoxon rank-sum test was performed for the increased multiples of C5-OH calculated in neonatal screening. RESULTS: Twenty one MCCC1 variants (14 novel) were identified in 37 cases, 6 MCCC2 variants (5 novel) in 4 cases. The increased multiple of C5-OH calculated in MCCC1-maternal-mutation and MCCC2-mutation groups were significantly higher than that in wild-type group (all P 0.05). CONCLUSIONS: Mutations on MCCC1 and MCCC2 genes are the major genetic causes for the increased C5-OH in neonates, and maternal single heterozygous mutation can contribute to the moderately to severely increased C5-OH.