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Deletion of Gene Could Increase Risk of Autism

Libby Brooks
Simons Simplex Collection Assistant Project Manager
Date Published: 
September 17, 2012

In different laboratories on opposite sides of the U.S., two researchers were waiting. Both had been involved with the Simons Simplex Collection (SSC), a major autism research initiative collecting genetic material from families with just one child on the autism spectrum. The time had come to analyze this highly polished data.

Sifting through the genome and finding a helpful clue

Dr. Arthur Beaudet, principal investigator for Baylor College of Medicine’s SSC site, and Dr. Matthew State, a collaborator at Yale University, set out to sequence the complete genome of 100 SSC “trios” -- families in which a mother, a father, and their child with an autism spectrum disorder (ASD) had provided a genetic sample. For this pilot study, the researchers used only samples from families in which the child is male.

Despite general acceptance in the scientific community that ASD has strong genetic A photograph of a family and their catunderpinnings, a clear genetic cause has not yet been identified in most affected individuals. Drs. Beaudet and State were looking for a pattern that might help them find where in the genome this keystone exists. They focused their efforts on the exome, the 1% or so of our DNA that contains vitally important protein-coding genes.1,2 Their intensive efforts turned up a deletion (some genetic material is missing) of the trimethyllysine hydroxylase epsilon gene (or TMLHE for short).

The researchers looked for the TMLHE gene in males who do and do not have an ASD. They found that the deletion appears to be fairly common, occurring in as many as 1 in 366 unaffected males. Surprisingly, though, the deletion appears to be nearly three times more common in families with two or more boys on the autism spectrum than it is in families with no children or only one child on the autism spectrum. The researchers therefore hypothesized that a deletion of the TMLHE gene puts a person at higher risk for developing an ASD. Like all scientific hypotheses, this finding needs to be replicated and studied further.

Impaired carnitine synthesis: affecting development

This particular deletion in TMLHE lowers a person’s ability to naturally synthesize carnitine, a common nutrient that is essential for mitochondrial function. Mitochondria are the structures inside our cells that supply the cells with energy. For mitochondria to power the cells effectively, they need a certain amount of carnitine. Besides being synthesized by TMLHE, most of the carnitine in the body comes from our diet. Red meat has the most carnitine, but it is also found in other meats, dairy products, and some whole grains. Getting enough carnitine is not generally an issue, except for those people who cannot synthesize their own carnitine.3

Dr. Beaudet applauds the SSC families because without them his team wouldn’t have been able to find this deletion. The families’ participation, and the careful collection of information and samples during the SSC project, made it possible not just to study the individuals with ASD and the deletion, but also ten healthy SSC fathers with the same genetic deletion who served as controls.

Next steps

Thanks to techniques developed in the past five to ten years, human genetics research has expanded and improved rapidly. Armed with these new techniques, the investigators have high hopes they will find some clues to help unravel the mystery of autism. The carnitine study is just one such example.

Dr. Beaudet is recruiting for a study that will further explore the connection between carnitine and ASD. He and his team at Baylor College of Medicine/Texas Children’s Hospital are interested in the effect of carnitine supplementation in young children with autism. Their hypothesis is that a child with ASD who is missing the TMLHE gene will show improvements in behavior after taking carnitine supplements. If further research provides substantial evidence of this carnitine connection, this will be a new and exciting area to explore in the realm of autism causes and treatments.

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  1. Ng, S. B., Turner, E. H., Robertson, P. D., Flygare, S. D., Bigham, A. W., Lee, C., et al. (2009). Targeted capture and massively parallel sequencing of 12 human exomes. Nature, 461(7261), 272-276. View Abstract
  2. Ng, S. B., Buckingham, K. J., Lee, C., Bigham, A. W., Tabor, H. K., Dent, K. M., et al. (2010). Exome sequencing identifies the cause of a Mendelian disorder. Nature Genetics, 42(1), 30-35. View Abstract
  3. Celestino-Soper, et al (2011).  A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism.  PNAS May 22, 2012.  Vol. 109 No. 21,  7974-7981. View Abstract