title: Next generation sequencing of patients with mut methylmalonic aciduria: Validation of somatic cell studies and identification of 16 novel mutations.
abstract: Mutations in the MUT gene, which encodes the mitochondrial enzyme methylmalonyl-CoA mutase, are responsible for the mut form of methylmalonic aciduria (MMA). In this study, a next generation sequencing (NGS) based gene panel was used to analyze 53 patients that had been diagnosed with mut MMA by somatic cell complementation analysis. A total of 54 different mutations in MUT were identified in 48 patients; 16 novel mutations were identified, including 1 initiation site mutation (c.2T>C [p.M1?]), 1 missense mutation (c.566A>T [p.N189I]), 2 nonsense mutations (c.129G>A [p.W43*] and c.1975C>T [p.Q659*]), 2 mutations affecting splice sites (c.753+3A>G and c.754-2A>G), 8 small insertions, deletions, and duplications (c.29dupT [p.L10Ffs*39], c.55dupG [p.V19Gfs*30], c.631_633delGAG [p.E211del], c.795_796insT [p.M266Yfs*7], c.1061delCinsGGA [p.S354Wfs*20], c.1065_1068dupATGG [p.S357Mfs*5], c.1181dupT [p.L394Ffs*30], c.1240delG [p.E414Kfs*17]), a large insertion (c.146_147ins279), and a large deletion involving exon 13. Phenotypic rescue and cDNA analysis were used to confirm that the c.146_147ins279 and c.631_633delGAG mutations were associated with the decreased methylmalonyl-CoA mutase function observed in the patient fibroblasts. In five patients, the NGS panel did not confirm the diagnosis made by complementation analysis. One of these patients was found to carry 2 novel mutations (c.433G > A [p.E145K] and c.511A>C [p.N171H]) in the SUCLG1 gene.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Jordan
authors.initials: J
authors.lastname: Chu
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Pupavac
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.affiliation: Department of Molecular Genetics, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Xia
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Molecular Genetics, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Molecular Genetics, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Stella
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Molecular Genetics, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Remington
authors.initials: R
authors.lastname: Fenter
authors.affiliation: Department of Molecular Genetics, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Zhang
authors.affiliation: Department of Molecular Genetics, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Genetics, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Lee-Jun
authors.initials: LJ
authors.lastname: Wong
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada. Electronic address: david.rosenblatt@mgcill.ca.
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
mesh_terms: D000293:Adolescent; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D007223:Infant; D008297:Male; D008764:Methylmalonic Acid / Q000378:metabolism; D008765:Methylmalonyl-CoA Mutase / Q000235:genetics*; D008928:Mitochondria / Q000201:enzymology; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D017384:Sequence Deletion / Q000235:genetics; D013389:Succinate-CoA Ligases / Q000235:genetics; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D008764:Methylmalonic Acid; D008765:Methylmalonyl-CoA Mutase; C000611245:SUCLG1 protein, human; D013389:Succinate-CoA Ligases
keywords: Methylmalonic aciduria; Methylmalonyl-CoA mutase; Next generation sequencing; Vitamin B(12); mut