Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing

Yong-hui Jiang, et al., Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing, The American Journal of Human Genetics 93 (2013)

Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked of autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations).

Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes.

The fist beneficiaries of genetic tests are young children, in whom formal diagnosis based on early behavioral signs can be challenging but who benefit most from earlier behavioral intervention. Understanding the genetic causes of ASD in an individual also potentially informs prognosis, medical management, and familial-recurrence risk assessment, and it can potentially facilitate drug-intervention trials through stratification based on genetic-pathway profiles.

When one combines all of the data from these complementary approaches, the picture remains incomplete: the etiological basis of about 20% of cases of ASD, at most can be explained to date. High heritability estimates (37%-90%) and family studies reconfirm strong genetic contributions and suggest that more genetic variants remain to be discovered.

We found that the number of de novo mutations was significantly correlated with paternal age, but not with maternal age.

In the autosomal regions, we found that WGS covered at least 10.8% more annotated eons than WES did. Furthermore, 9.2% (11/119) of ASD-linked genes have at least one exon untargeted by the most widely used capture kit currently available for exome sequencing. A more detailed comparison between the two technologies’ coverage in the coding regions showed that WGS captured 2.7% more annotated coding eons with coverage sufficient for variant calling (>5x) than did WES. The coverage difference was even more prominent for the X chromosome and gene splice sites. the former of which carries a disproportionate number of ASD susceptibility genes.

In the future, results of WGS might allow earlier diagnosis of ASD, especially in siblings, for whom recurrence rates are approximately 18%.

The X-linked gene mutations also help to explain the male gender bias observed in ASD.

At least 17.5% more annotated eons (5.7% more coding) were covered by WGS than by WES.

However, calling CNVs from WGS remains a challenge. Using a read depth-based approach for CNV detection, we found that as many as 88% of the calls could be false positives.


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