title: Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD.
abstract: OBJECTIVE
  3-Methylcrotonyl-CoA carboxylase deficiency (MCCD) is an autosomal recessive disorder of leucine catabolism that has a highly variable clinical phenotype, ranging from acute metabolic acidosis to nonspecific symptoms such as developmental delay, failure to thrive, hemiparesis, muscular hypotonia, and multiple sclerosis. Implementation of newborn screening for MCCD has resulted in broadening the range of phenotypic expression to include asymptomatic adults. The purpose of this study was to identify factors underlying the varying phenotypes of MCCD.
  
  
  METHODS
  We performed exome sequencing on DNA from 33 cases and 108 healthy controls. We examined these data for associations between either MCC mutational status, genetic ancestry, or consanguinity and the absence or presence/specificity of clinical symptoms in MCCD cases.
  
  
  RESULTS
  We determined that individuals with nonspecific clinical phenotypes are highly inbred compared with cases that are asymptomatic and healthy controls. For 5 of these 10 individuals, we discovered a homozygous damaging mutation in a disease gene that is likely to underlie their nonspecific clinical phenotypes previously attributed to MCCD.
  
  
  CONCLUSIONS
  Our study shows that nonspecific phenotypes attributed to MCCD are associated with consanguinity and are likely not due to mutations in the MCC enzyme but result from rare homozygous mutations in other disease genes.Genet Med 17 8, 660-667.
authors.affiliation: Department of Pediatrics, Rady Children's Hospital, University of California, San Diego, La Jolla, California, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Shepard
authors.affiliation: 1] Department of Pediatrics, Rady Children's Hospital, University of California, San Diego, La Jolla, California, USA [2] Clinical and Translational Research Institute, University of California, San Diego, La Jolla, California, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Barshop
authors.affiliation: 1] Division of Metabolic Diseases and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland [2] Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Matthias R
authors.identifier: 0000000292700826
authors.initials: MR
authors.lastname: Baumgartner
authors.affiliation: Department of Clinical Medicine, University of Tromsø, Tromsø, Norway.
authors.forename: John-Bjarne
authors.initials: JB
authors.lastname: Hansen
authors.affiliation: 1] Department of Pediatrics, Rady Children's Hospital, University of California, San Diego, La Jolla, California, USA [2] Clinical and Translational Research Institute, University of California, San Diego, La Jolla, California, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Jepsen
authors.affiliation: 1] Department of Pediatrics, Rady Children's Hospital, University of California, San Diego, La Jolla, California, USA [2] Clinical and Translational Research Institute, University of California, San Diego, La Jolla, California, USA.
authors.forename: Erin N
authors.initials: EN
authors.lastname: Smith
authors.affiliation: 1] Department of Pediatrics, Rady Children's Hospital, University of California, San Diego, La Jolla, California, USA [2] Clinical and Translational Research Institute, University of California, San Diego, La Jolla, California, USA [3] Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Frazer
mesh_terms: D000328:Adult; D000483:Alleles; D019735:Carbon-Carbon Ligases / Q000172:deficiency* / Q000235:genetics; D016022:Case-Control Studies; D003241:Consanguinity; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D015997:Neonatal Screening; D056806:Urea Cycle Disorders, Inborn / Q000201:enzymology / Q000235:genetics*
chemical_list: D019735:Carbon-Carbon Ligases; C021573:methylcrotonoyl-CoA carboxylase