title: Added value of next generation gene panel analysis for patients with elevated methylmalonic acid and no clinical diagnosis following functional studies of vitamin B12 metabolism.
abstract: Next generation sequencing (NGS) based gene panel testing is increasingly available as a molecular diagnostic approach for inborn errors of metabolism. Over the past 40 years patients have been referred to the Vitamin B12 Clinical Research Laboratory at McGill University for diagnosis of inborn errors of cobalamin metabolism by functional studies in cultured fibroblasts. DNA samples from patients in which no diagnosis was made by these studies were tested by a NGS gene panel to determine whether any molecular diagnoses could be made. 131 DNA samples from patients with elevated methylmalonic acid and no diagnosis following functional studies of cobalamin metabolism were analyzed using the 24 gene extended cobalamin metabolism NGS based panel developed by Baylor Miraca Genetics Laboratories. Gene panel testing identified two or more variants in a single gene in 16/131 patients. Eight patients had pathogenic findings, one had a finding of uncertain significance, and seven had benign findings. Of the patients with pathogenic findings, five had mutations in ACSF3, two in SUCLG1 and one in TCN2. Thus, the NGS gene panel allowed for the presumptive diagnosis of 8 additional patients for which a diagnosis was not made by the functional assays.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Pupavac
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, TX, United States.
authors.forename: Xia
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Jordan
authors.initials: J
authors.lastname: Chu
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, TX, United States.
authors.forename: Guoli
authors.initials: G
authors.lastname: Wang
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, TX, United States.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, TX, United States.
authors.forename: Stella
authors.initials: S
authors.lastname: Chen
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, TX, United States.
authors.forename: Remington
authors.initials: R
authors.lastname: Fenter
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, TX, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Zhang
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, TX, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, TX, United States; Department of Molecular and Human 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@mcgill.ca.
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics; D002675:Child, Preschool; D003066:Coenzyme A Ligases / Q000235:genetics; D005260:Female; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008661:Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics*; D008764:Methylmalonic Acid / Q000378:metabolism*; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D010641:Phenotype; D013389:Succinate-CoA Ligases / Q000235:genetics; D014805:Vitamin B 12 / Q000378:metabolism*; D014806:Vitamin B 12 Deficiency / Q000175:diagnosis* / Q000235:genetics*; D014803:Vitamin B Complex / Q000378:metabolism*
chemical_list: D014803:Vitamin B Complex; D008764:Methylmalonic Acid; C561770:ACSF3 protein, human; D003066:Coenzyme A Ligases; C000611245:SUCLG1 protein, human; D013389:Succinate-CoA Ligases; D014805:Vitamin B 12
keywords: Cobalamin metabolism; Diagnostic test; Functional studies; Methylmalonic acid; Next generation sequencing gene panel; Vitamin B(12)