Background:  De novo mutations that spontaneously arise in sperm or eggs and are subsequently transmitted from parents to children are thought to play a critical role in human disease, including autism spectrum disorder (ASD).  In order to better assess the importance of de novo mutations in the genetics of ASD, it is necessary to understand what internal and external factors influence the onset of such variation.

What’s new:  In a recent report in Cell, whole-genome sequencing was performed on ten pairs on monozygotic twins concordant with ASD and their parents.  Whole-genome sequencing allows for the detection of genetic variation throughout the human genome, not only in genes.  Sequencing of parental samples was performed to identify de novo mutations present in both monozygotic twins.

In agreement with recent ASD sequencing studies, paternal age was found to play a significant role in genome-wide variation, with the children of older fathers tending to have a greater number of de novo mutations.  Rather than being randomly distributed throughout the genome, de novo mutations were more likely to be located in genomic “hot-spots” where the intrinsic properties of the DNA within these regions contributed to increased mutability.  A number of genes and genomic regions that have been previously associated with ASD, such as the NRXN1 gene and the 15q11-q13 chromosomal region, were found to have elevated de novo mutation rates.

Why it’s important:  These findings provide a better understanding of the factors that are responsible for ASD-associated de novo genetic variation. As DNA sequencing and analysis technology continues to progress, cataloguing ASD-linked “hot spots” in the human genome may aid in the development of screening and/or diagnostic genetic testing for autism.

Genetic Testing

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