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Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE
- Source :
- Translational Psychiatry
- Publication Year :
- 2012
- Publisher :
- Springer Science and Business Media LLC, 2012.
-
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.
- 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
Subjects
Details
- ISSN :
- 21583188
- Volume :
- 2
- Database :
- OpenAIRE
- Journal :
- Translational Psychiatry
- Accession number :
- edsair.doi.dedup.....d3f6999324995bf2f8ed7cdcb9ede833