title: Genetic analysis of impaired trimethylamine metabolism using whole exome sequencing.
abstract: BACKGROUND
  Trimethylaminuria (TMAU) is a genetic disorder whereby people cannot convert trimethylamine (TMA) to its oxidized form (TMAO), a process that requires the liver enzyme FMO3. Loss-of-function variants in the FMO3 gene are a known cause of TMAU. In addition to the inability to metabolize TMA precursors like choline, patients often emit a characteristic odor because while TMAO is odorless, TMA has a fishy smell. The Monell Chemical Senses Center is a research institute with a program to evaluate people with odor complaints for TMAU.
  
  
  METHODS
  Here we evaluated ten subjects by (1) odor evaluation by a trained sensory panel, (2) analysis of their urine concentration of TMA relative to TMAO before and after choline ingestion, and (3) whole exome sequencing as well as subsequent variant analysis of all ten samples to investigate the genetics of TMAU.
  
  
  RESULTS
  While all subjects reported they often emitted a fish-like odor, none had this malodor during sensory evaluation. However, all were impaired in their ability to produce >90% TMAO/TMA in their urine and thus met the criteria for TMAU. To probe for genetic causes, the exome of each subject was sequenced, and variants were filtered by genes with a known (FMO3) or expected effect on TMA metabolism function (other oxidoreductases). We filtered the remaining variants by allele frequency and predicated functional effects. We identified one subject that had a rare loss-of-function FMO3 variant and six with more common decreased-function variants. In other oxidoreductases genes, five subjects had four novel rare single-nucleotide polymorphisms as well as one rare insertion/deletion. Novel in this context means no investigators have previously linked these variants to TMAU although they are in dbSNP.
  
  
  CONCLUSIONS
  Thus, variants in genes other than FMO3 may cause TMAU and the genetic variants identified here serve as a starting point for future studies of impaired TMA metabolism.
authors.affiliation: Center for Applied Genomics, the Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Abramson Res Cntr, Ste 1016H, Philadelphia, PA, 19104, USA. guoy@email.chop.edu.
authors.forename: Yiran
authors.identifier: http://orcid.org/0000-0002-6549-8589
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Monell Chemical Senses Center, 3500 Market St, Philadelphia, PA, 19104, USA.
authors.forename: Liang-Dar
authors.initials: LD
authors.lastname: Hwang
authors.affiliation: BGI-Shenzhen, Shenzhen, 518083, China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Li
authors.affiliation: Monell Chemical Senses Center, 3500 Market St, Philadelphia, PA, 19104, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Eades
authors.affiliation: Monell Chemical Senses Center, 3500 Market St, Philadelphia, PA, 19104, USA.
authors.forename: Chung Wen
authors.initials: CW
authors.lastname: Yu
authors.affiliation: Monell Chemical Senses Center, 3500 Market St, Philadelphia, PA, 19104, USA.
authors.forename: Corrine
authors.initials: C
authors.lastname: Mansfield
authors.affiliation: Monell Chemical Senses Center, 3500 Market St, Philadelphia, PA, 19104, USA.
authors.forename: Alexis
authors.initials: A
authors.lastname: Burdick-Will
authors.affiliation: Center for Applied Genomics, the Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Abramson Res Cntr, Ste 1016H, Philadelphia, PA, 19104, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chang
authors.affiliation: BGI-Shenzhen, Shenzhen, 518083, China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Monell Chemical Senses Center, 3500 Market St, Philadelphia, PA, 19104, USA.
authors.forename: Fujiko F
authors.initials: FF
authors.lastname: Duke
authors.affiliation: BGI-Shenzhen, Shenzhen, 518083, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Fakharzadeh
authors.affiliation: University of Colorado Health Sciences Center, Denver, CO, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Fennessey
authors.affiliation: Center for Applied Genomics, the Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Abramson Res Cntr, Ste 1016H, Philadelphia, PA, 19104, USA.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.affiliation: BGI-Shenzhen, Shenzhen, 518083, China.|Shenzhen Key Laboratory of Genomics, Shenzhen, 518083, China.|The Guangdong Enterprise Key Laboratory of Human Disease Genomics, Shenzhen, 518083, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Center for Applied Genomics, the Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Abramson Res Cntr, Ste 1016H, Philadelphia, PA, 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Monell Chemical Senses Center, 3500 Market St, Philadelphia, PA, 19104, USA. reed@monell.org.
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Reed
authors.affiliation: Monell Chemical Senses Center, 3500 Market St, Philadelphia, PA, 19104, USA.|Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: George
authors.initials: G
authors.lastname: Preti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002794:Choline / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D008661:Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics*; D008744:Methylamines / Q000378:metabolism / Q000652:urine*; D008875:Middle Aged; D010105:Oxygenases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D012903:Smell
chemical_list: D008744:Methylamines; D004247:DNA; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C023336:trimethylamine; D002794:Choline