Dingwen Wu1, Bin Lu2, Jianbin Yang1, Rulai Yang1, Xinwen Huang1, Fan Tong1, Jing Zheng1, Zhengyan Zhao1. 1. Zhejiang Neonatal Screening Center, Department of Genetics and Metabolism, the Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China. 2. Zhejiang Biosan Biochemical Technologies Co. Ltd, Hangzhou 310012, China.
Abstract
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), while there was no significant difference between MCCC1-paternal-mutation group and wild-type group (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.
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), while there was no significant difference between MCCC1-paternal-mutation group and wild-type group (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.
Authors: Sarah Catharina Grünert; Sonja Marina Schlatter; Robert Niklas Schmitt; Corinne Gemperle-Britschgi; Lenka Mrázová; Mehmet Cihan Balcı; Felix Bischof; Mahmut Çoker; Anibh M Das; Mübeccel Demirkol; Maaike de Vries; Gülden Gökçay; Johannes Häberle; Sema Kalkan Uçar; Amelie Sophia Lotz-Havla; Thomas Lücke; Dominique Roland; Frank Rutsch; René Santer; Andrea Schlune; Christian Staufner; Karl Otfried Schwab; Grant A Mitchell; Jörn Oliver Sass Journal: Mol Genet Metab Date: 2017-05-22 Impact factor: 4.797
Authors: Sarah C Grünert; Martin Stucki; Raphael J Morscher; Terttu Suormala; Celine Bürer; Patricie Burda; Ernst Christensen; Can Ficicioglu; Jürgen Herwig; Stefan Kölker; Dorothea Möslinger; Elisabetta Pasquini; René Santer; K Otfried Schwab; Bridget Wilcken; Brian Fowler; Wyatt W Yue; Matthias R Baumgartner Journal: Orphanet J Rare Dis Date: 2012-05-29 Impact factor: 4.123