Analyzing genetics using the tissues of people with autism can provide deeper insight into the disorder than performing genetic techniques on DNA samples alone. Arthur Beaudet and his colleagues at Baylor College of Medicine in Houston propose two projects that examine autism genetics in the context of the physiology of the disorder.

Haploinsufficiency, or the loss of one copy of a gene or genomic region, can have a large effect by reducing production of messenger RNA and by creating complete reliance on the remaining allele, which may contain a mutation.

The researchers are investigating whether autism and schizophrenia are associated with aberrant epigenetic modifications, including methylation of the DNA, that silence one allele of a gene. Epigenetic silencing of an allele is likely to have the same effect as deletion of or a loss-of-function mutation in that allele. These methylation patterns are best preserved in tissue samples, leading the researchers to perform a genome-wide analysis of DNA methylation on postmortem samples from the cerebellum and cortex.

So far, the researchers have found that the sequence of cytosine and guanine — CpG islands — in the SERHL gene are hypermethylated in one individual with autism compared with reference samples. They also identified hypermethylated CpG islands in the predicted gene LOC652276 in one person with schizophrenia. The disease significance of these differences is not yet known.

Human males have only one X chromosome, making them more susceptible to the effects of mutations in X-linked genes, such as color blindness and hemophilia. Beaudet and his colleagues also propose to study the effects of a deletion in an X-linked gene, TMLHE, which they associated with autism through samples from the Simons Simplex Collection. TMLHE deficiency resulting from this deletion is common in normal males (1 in about 350), but the researchers found that the deletion is 3.4 times more frequent in families with autism, strongly suggesting a link to the disorder. TMLHE encodes the first enzyme in the synthesis of the micronutrient carnitine, which is essential for mitochondrial function and energy metabolism. Neurons have substantial energetic needs, and the researchers hypothesize that the metabolic strains of carnitine deficiency may underlie some aspects of autism. If some forms of autism involve carnitine deficiency, they may be preventable though dietary supplementation with carnitine.