title: Heterozygous FA2H mutations in autism spectrum disorders.
abstract: BACKGROUND
  Widespread abnormalities in white matter development are frequently reported in cases of autism spectrum disorders (ASD) and could be involved in the disconnectivity suggested in these disorders. Homozygous mutations in the gene coding for fatty-acid 2-hydroxylase (FA2H), an enzyme involved in myelin synthesis, are associated with complex leukodystrophies, but little is known about the functional impact of heterozygous FA2H mutations. We hypothesized that rare deleterious heterozygous mutations of FA2H might constitute risk factors for ASD.
  
  
  METHODS
  We searched deleterious mutations affecting FA2H, by genotyping 1256 independent patients with ASD genotyped using Genome Wide SNP arrays, and also by sequencing in independent set of 186 subjects with ASD and 353 controls. We then explored the impact of the identified mutations by measuring FA2H enzymatic activity and expression, in transfected COS7 cells.
  
  
  RESULTS
  One heterozygous deletion within 16q22.3-q23.1 including FA2H was observed in two siblings who share symptoms of autism and severe cognitive impairment, axial T2-FLAIR weighted MRI posterior periventricular white matter lesions. Also, two rare non-synonymous mutations (R113W and R113Q) were reported. Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells.
  
  
  CONCLUSIONS
  While our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Scheid
authors.forename: Anna
authors.initials: A
authors.lastname: Maruani
authors.forename: Guillaume
authors.initials: G
authors.lastname: Huguet
authors.forename: Claire S
authors.initials: CS
authors.lastname: Leblond
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nygren
authors.forename: Henrik
authors.initials: H
authors.lastname: Anckarsäter
authors.forename: Anita
authors.initials: A
authors.lastname: Beggiato
authors.forename: Maria
authors.initials: M
authors.lastname: Rastam
authors.forename: Fréderique
authors.initials: F
authors.lastname: Amsellem
authors.forename: I Carina
authors.initials: IC
authors.lastname: Gillberg
authors.forename: Monique
authors.initials: M
authors.lastname: Elmaleh
authors.forename: Marion
authors.initials: M
authors.lastname: Leboyer
authors.forename: Christopher
authors.initials: C
authors.lastname: Gillberg
authors.forename: Catalina
authors.initials: C
authors.lastname: Betancur
authors.forename: Mary
authors.initials: M
authors.lastname: Coleman
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hama
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.forename: Thomas
authors.initials: T
authors.lastname: Bourgeron
authors.affiliation: Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France. richard.delorme@rdb.aphp.fr.
authors.forename: Richard
authors.initials: R
authors.lastname: Delorme
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D019556:COS Cells; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D015331:Cohort Studies; D017353:Gene Deletion; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011859:Radiography; D012307:Risk Factors; D017422:Sequence Analysis, DNA
chemical_list: D006899:Mixed Function Oxygenases; C019081:fatty acid alpha-hydroxylase