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September 23, 2019

Disease predisposition risk: what to consider beyond cancer

In our previous post, we took a look at screening for cancer predisposition risk. Specifically delving into coverage of breast cancer risk variants in the BRCA1 and BRCA2 genes as well as other genes by different types of genetic tests.

Today, we’re taking a look at disease predisposition risk for conditions other than cancer. We know that at home DNA tests are everywhere these days, offering to provide information about not just our ancestry but also our health. These can include a wide range of conditions including two that we’ll focus on here: hemochromatosis and alpha-1 trypsin deficiency.

Predisposition to iron overload with hemochromatosis

We’re often familiar with our body’s need for iron and the importance of incorporating iron-rich foods such as spinach and legumes into our diet, particularly if we’re trying to cut back on iron-rich sources of animal protein. But too much iron can also be problematic as excess stored iron, or iron overload, can lead to organ or tissue damage. Hemochromatosis is a genetic disorder that causes people to absorb too much iron from their diet. Affecting roughly 1 in 200 people of northern European descent, hemochromatosis often goes undiagnosed yet is readily treated once recognized.

Direct-to-consumer testing services like 23andMe and others look at only a small number of variants in the HFE gene, often as few as 2 variants. It’s important to know that the HFE gene has more than 40 different variants that have been reported to be associated with hemochromatosis. And that while variants in the HFE gene cause the most common form (type 1), there are three additional forms that are caused by variants in other genes: type 2 caused by variants in the HJV or HAMP genes, type 3 caused by variants in the TFR2 gene and type 4 caused by variants in the SLC40A1 gene.

About alpha-1 trypsin deficiency and predisposition to liver and lung disease

Alpha-1 is a protein produced by the liver that works to protect our lungs from inflammation caused by infection or inhalation of irritants like smoke. But when too much alpha-1 is present, as in people with alpha-1 trypsin deficiency, it can end up causing damage to the lungs resulting in complications like recurrent lung infections and chronic obstructive pulmonary disease (COPD). And in some cases can lead to liver damage. Some direct-to-consumer tests screen for variants in the causal SERPNA1 gene, but often as few as 2 variants even though more than 60 deleterious variants have been identified.

Clinical tests provide significantly more comprehensive and reliable results when compared to direct-to-consumer tests, but even they are affected by the choice of sequencing technology used. Most employ technologies that cover only 0.02% to 2% of an individual’s DNA. This means that certain types of complex disease predisposition risk variants will be missed, and that certain genes might not be included at all.

The difference seen with WGS based testing

In contrast, with a whole genome sequencing (WGS) based test like Genomic Inform®, our entire DNA is sequenced so that these blind spots are avoided. The result of using better sequencing technology is that hemochromatosis testing and alpha-1 trypsin deficiency testing isn’t limited to 2 variants each. Instead, dozens of additional causative variants, including those in additional genes, will be identified.