1. Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE
- Author
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Didier Périsse, Clement A. Gautier, Guillaume Huguet, Anne Faudet, Claudine Laurent, C Dupuits, Christopher Gillberg, Delphine Bouteiller, Cyril Mignot, Delphine Héron, Sandra Whalen, David Cohen, Mylène Gilleron, Marion Leboyer, Boris Keren, Thomas Bourgeron, Marion Gérard, Alexis Brice, C. Depienne, Alexandra Afenjar, Agnès Rastetter, Foudil Lamari, Richard Delorme, Aurélia Jacquette, Caroline Nava, S Caillet, and Bruno Leheup
- Subjects
Adult ,Male ,Candidate gene ,TMLHE ,Nonsense mutation ,Biology ,medicine.disease_cause ,Polymerase Chain Reaction ,Mixed Function Oxygenases ,Cohort Studies ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Genes, X-Linked ,medicine ,Humans ,Missense mutation ,Exome ,Family ,Sex Distribution ,Child ,Genetic Association Studies ,Biological Psychiatry ,X chromosome ,030304 developmental biology ,Genetics ,Chromosomes, Human, X ,0303 health sciences ,Mutation ,carnitine ,Autism spectrum disorders ,medicine.disease ,Psychiatry and Mental health ,Child Development Disorders, Pervasive ,male excess ,Case-Control Studies ,chromosome X ,Autism ,Original Article ,next-generation sequencing ,Female ,030217 neurology & neurosurgery - 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.
- Published
- 2012