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Study Points to Possible Role for Recessive Inherited Factors in Some Autism Cases

NEW YORK (GenomeWeb News) – A subset of autism cases — particularly amongst those characterized by pronounced intellectual disability — seems to stem from large stretches of similar sequence that are inherited from each parent, according to a study out online this week in the American Journal of Human Genetics.

"Autism is a very broad, heterogeneous condition," Brown University's Eric Morrow, senior author on the study, said in a statement. "With genomics, we've begun to be able to dissect the heterogeneity into smaller groupings."

Morrow led a group of researchers from Brown University and elsewhere who analyzed array-based genotyping information for more than 2,100 individuals with simplex autism, a form of the condition in which one child in a family is affected by autism spectrum disorder, or ASD, though his or her parents and siblings are not.

The group's search for recessive inherited factors in ASD focused on "runs of homozygosity" that occur in the genome when children inherit relatively rare but matching stretches of DNA sequence from both parents — a situation that's known to be more common-than-usual in individuals affected by intellectual disability alone.

Using three different Illumina arrays, investigators genotyped individuals from 2,108 ASD-affected families from the Simons Simplex Collection. When they used this data to look for runs of homozygosity, they found that some individuals with ASD carried an unusually high number of large runs of homozygosity (those spanning 2.5 million bases or more) in their genomes.

But the over-representation did not turn up across the board in the ASD cases. Instead, the large runs of homozygosity were most common amongst cases with especially low scores on intelligence tests and in girls with ASD, who often had intellectual disability as well.

The latter finding was intriguing, study authors noted, since autism as a whole is much more common in boys than it is in girls. But it's too soon to tell whether that association is due to the higher frequency with which intellectual disability is detected in the girls with ASD.

"Our study presents among the first data to suggest that the genetic susceptibility to the disorder may have some distinct aspects in girls and in 'lower-functioning' autism," first author Ece Gamsiz, a researcher affiliated with Brown University and Rhode Island Hospital's Norman Prince Neurosciences Institute, said in a statement.

In contrast, brothers and sisters of the children with ASD and intellectual disability seemed to carry far fewer runs of homozygosity in their genomes, as did individuals with ASD who had not been diagnosed with intellectual disability.

"Overall, our analysis supports significant differences in the genetic architecture for children with autism and low IQ," Morrow, Gamsiz, and co-authors concluded. "Although other causes are possible, the simplest explanation for increased [runs of homozygosity] is that autosomal-recessive loci play an important part in the genetic susceptibility to autism with co-occurring [intellectual disability]."

A number of past studies have uncovered de novo mutations and copy number changes in some individuals with ASD, indicating that at least some ASD cases occur as a consequence of genetic changes not found in either parent. On the other hand, a pair of exome sequencing studies published earlier this year highlighted a potential role for recessive, inherited mutations from each parent that, when combined in the affected child, interfere with the function of certain genes.