title: Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.
abstract: The striking excess of affected males in autism spectrum disorders (ASD) suggests that genes located on chromosome X contribute to the etiology of these disorders. To identify new X-linked genes associated with ASD, we analyzed the entire chromosome X exome by next-generation sequencing in 12 unrelated families with two affected males. Thirty-six possibly deleterious variants in 33 candidate genes were found, including PHF8 and HUWE1, previously implicated in intellectual disability (ID). A nonsense mutation in TMLHE, which encodes the ɛ-N-trimethyllysine hydroxylase catalyzing the first step of carnitine biosynthesis, was identified in two brothers with autism and ID. By screening the TMLHE coding sequence in 501 male patients with ASD, we identified two additional missense substitutions not found in controls and not reported in databases. Functional analyses confirmed that the mutations were associated with a loss-of-function and led to an increase in trimethyllysine, the precursor of carnitine biosynthesis, in the plasma of patients. This study supports the hypothesis that rare variants on the X chromosome are involved in the etiology of ASD and contribute to the sex-ratio disequilibrium.
authors.affiliation: INSERM, U975-CRICM, Institut du cerveau et de la moelle épinière (ICM), Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Nava
authors.forename: F
authors.initials: F
authors.lastname: Lamari
authors.forename: D
authors.initials: D
authors.lastname: Héron
authors.forename: C
authors.initials: C
authors.lastname: Mignot
authors.forename: A
authors.initials: A
authors.lastname: Rastetter
authors.forename: B
authors.initials: B
authors.lastname: Keren
authors.forename: D
authors.initials: D
authors.lastname: Cohen
authors.forename: A
authors.initials: A
authors.lastname: Faudet
authors.forename: D
authors.initials: D
authors.lastname: Bouteiller
authors.forename: M
authors.initials: M
authors.lastname: Gilleron
authors.forename: A
authors.initials: A
authors.lastname: Jacquette
authors.forename: S
authors.initials: S
authors.lastname: Whalen
authors.forename: A
authors.initials: A
authors.lastname: Afenjar
authors.forename: D
authors.initials: D
authors.lastname: Périsse
authors.forename: C
authors.initials: C
authors.lastname: Laurent
authors.forename: C
authors.initials: C
authors.lastname: Dupuits
authors.forename: C
authors.initials: C
authors.lastname: Gautier
authors.forename: M
authors.initials: M
authors.lastname: Gérard
authors.forename: G
authors.initials: G
authors.lastname: Huguet
authors.forename: S
authors.initials: S
authors.lastname: Caillet
authors.forename: B
authors.initials: B
authors.lastname: Leheup
authors.forename: M
authors.initials: M
authors.lastname: Leboyer
authors.forename: C
authors.initials: C
authors.lastname: Gillberg
authors.forename: R
authors.initials: R
authors.lastname: Delorme
authors.forename: T
authors.initials: T
authors.lastname: Bourgeron
authors.forename: A
authors.initials: A
authors.lastname: Brice
authors.forename: C
authors.initials: C
authors.lastname: Depienne
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D015331:Cohort Studies; D059472:Exome; D005190:Family; D005260:Female; D050172:Genes, X-Linked; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction; D017678:Sex Distribution
chemical_list: D006899:Mixed Function Oxygenases; C025931:trimethyl-lysine hydroxylase