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Genetics: Recessive mutations may contribute to autism

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Jessica Wright
3 September 2013

Risky inheritance: Long stretches of DNA that are identical on both copies of a chromosome are more prevalent in people with autism (red) than in their unaffected siblings (blue).

The genomes of people who have both autism and intellectual disability have more regions that may harbor recessive mutations than those of their unaffected siblings, according to a study published 11 July in the American Journal of Human Genetics1.

Recessive mutations lead to symptoms only when both copies of a gene are affected. That means that regions of DNA that are identical, or homozygous, on both copies of the chromosome may contain harmful mutations associated with autism. These homozygous regions arise as a result of shared ancestry, and so are prevalent in places where marriage between first cousins is common.

Many studies looking for autism-risk genes focus on de novo mutations, which arise spontaneously. The results of the new study suggest that inherited recessive mutations may also play a significant role in autism, especially when it’s accompanied by intellectual disability.

The researchers looked at 1,652 families from the Simons Simplex Collection (SSC), a database of families that have one child with autism and unaffected parents and siblings. The SSC is funded by the Simons Foundation, SFARI.org’s parent organization.

The researchers scanned the genomes of the children with autism and their siblings, looking for homozygous regions at least 2,500 kilobases (kb) long. Children who have autism and an intelligence quotient (IQ) of 70 or below have more of these regions than their unaffected siblings do, the study found. This is not the case for the children with autism who have an IQ above 70.

Individuals with autism who carry at least one 2,500-kb homozygous region also have lower IQ scores than do those with autism who do not have those regions. These two groups of individuals have equivalent symptoms otherwise, however. For example, girls with autism who have at least one of these regions have an average IQ of 74, whereas the average IQ for all individuals with autism in the study is about 82.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Gamsiz E.D. et al. Am. J. Hum. Genet. 93, 103-109 (2013) PubMed

Comments

Name: Mohammed Athari
4 September 2013 - 1:16AM

This study comprised of 2,108 North American simplex ASD-affected families. No controls were observed for neurotoxin exposure. The study argues that autosomal-recessive loci “might” have a contribution but when it compared total burden of autosomal homozygosity without regard to family, the study did NOT observe differences and the statistical significance for any given single locus failed to survive conservative genome-wide correction. The study admits that the mechanisms for supposed susceptibility “remain to be proven” and analysis of DNA sequence within ROH loci was not done to identify/distinguish these mechanisms.

Studies of genotoxicity for neurotoxins such as lead have consistently found associations with DNA damage and micronuclei formation. Cell culture studies support an epigenetic mechanism or co-mutagenic effects. Proteins depending upon sulfur-containing side chains for maintaining conformity or activity are vulnerable to inactivation by lead because of its strong sulfur-binding affinity. The enzyme, ALAD, a 280 kDa protein, is inducible and is the major Pb-binding protein within the erythrocyte. In human brain, Pb-binding proteins include thymosin β4 and an unidentified protein of 23 kDa. Animal toxicology studies demonstrated a role for metallothionein as a renal Pb-binding protein. Why would you not confound for toxicity? This study is nothing but speculation and surmise.

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