Conference Summary

Clinical Applications for Technological Advances in Genetic Testing

Shelley D. Smith, PhD


December 11, 2009

In This Article

A major theme running through the American Society of Human Genetics (ASHG) 59th Annual Meeting was how new technical developments and discoveries are aiding in the identification of genes and gene networks at the core of inherited disorders, especially complex disorders -- such as autism, cancers, and type 2 diabetes mellitus.


In the past few years, the development of large panels of single nucleotide polymorphisms (SNPs) has led to the discovery of genes that contribute to complex genetic disorders. However, these SNPs account for only a small part of the phenotypic variation in a complex disorder; additional genetic influences remain to be discovered.

This "missing heritability" is thought to be due in part to a basic feature in the design of the SNP arrays used in genome-wide association studies (GWAS). The arrays can include as many as 1 million SNPs, but, to be most useful in large populations, the SNPs are selected to have high allelic frequencies, such that the least frequent (minor) allele has a frequency of at least 5% in the population. This allows testing of the "common disease-common variant" hypothesis, which assumes that common diseases are due to the combined actions of common variants. The problem of missing heritability suggests that at least part of the variation in common complex disorders is actually due to rare variants, either rare SNPs or other types of mutations, and particularly mutations in noncoding regulatory regions. This has led to the search for rare variants, either through sequencing or the discovery of copy number variants (CNVs).

CNVs are small deletions or duplications of DNA that range in size from a few to hundreds of kilobases. These are not detectable by karyotypic analysis but are picked up on comparative genome hybridization arrays or on SNP arrays that are especially designed to include SNPs that can show runs of increased or decreased hybridization, indicating a loss or increase in copies.

Increased CNVs have been associated with schizophrenia and autism, and in some cases, these have been increased around genes already known to be candidates for these disorders. It is assumed that the CNVs disrupt the genes or regulatory regions and, thus, contribute to the causes of those disorders. Whole genome studies are showing that some CNVs are common in the general population. As indicated by reports from Matthew Hurles,[1] from the Sanger Center in the United Kingdom and Steven McCarroll,[2] from the Harvard Medical School in Boston, Massachusetts, common CNVs (at least as currently detected) appear to be benign and probably will not be involved in disease, although they may still be useful as markers. However, rare CNVs are more likely to have deleterious effects.

For example, Maja Bucan,[3] from the University of Pennsylvania in Philadelphia, reported on the use of CNVs in autism. To increase the probability of finding deleterious CNVs, the group focused on CNVs in exons or highly conserved noncoding sites that might serve as regulatory regions. In their analysis of the results, they further filtered the candidate genes to those involved in presynaptic neurons. One of the genes they identified, ROBO1, had an increased incidence of CNVs in intergenic regions in autistic probands. Interestingly, this gene has also been associated with another neurodevelopmental trait, developmental dyslexia.


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