Key genetics concepts

As a population we have not been effective in practicing preventative lifestyle medicine, other than diminishing the rate of smoking. Obesity is on the increase; our diet is suboptimal, and in general we are not exercising enough. The majority of the population is drinking outside the recommended limits for alcohol and we are not sleeping enough.

The hope is that if your personal gene profile suggests an increased risk of certain conditions, you will be better incentivised to positively change your lifestyle risks.

Genetics has the potential to have similar health benefits as with the other seismic health development eras, such as immunisation and in the 1940s the advent of antibiotics.

Penetrance of Genes

Finding a patient with a cancer who has a specific genetic alteration that contributes to that cancer is one thing. What is not so clearly known, is the significance when one finds such a genetic alteration in a healthy individual - without any significant family history. Little genetic work has been done in a healthy population, and it may be that in a healthy population the presence of such a genetic alteration does not have the same risks. The genetic alteration may only rarely express itself to cause disease as there may be other factors involved which we do not yet know about, which alter the effects of such deleterious genetic alterations.

The penetrance of cardiac genes may be quite low; if we consider cardiomyopathies (heart muscle disorders of genetic origin - i.e. not coronary artery disease), it maybe that only 10-20 percent of people who have a genetic alteration will actually develop it. This is called ‘reduced penetrance’. It is important not to cause unnecessary worry to patients.

In the 90 Sloane Street Study (90 S) all participants prior to genetic testing have an Echocardiogram – a heart ultrasound which looks at the heart muscle. If a participant is found to have a cardiomyopathy genetic alteration, but the Echocardiogram is normal (i.e. there are no signs of cardiomyopathy), we would just repeat the Echocardiogram in three years’ time.

Variants of Unknown Significance

These are changes in genes of which the significance is not clearly understood. Such variants may be in a particular gene that is known to cause certain conditions, but the reality is that probably only about 1 in 100 of VUS actually have clinical significance. 

Participants need the knowledge of a geneticist to give reassurance. For some people, it may be that when we look back in five years’ time, more is known about the variant and its potential pathogenicity, or more likely benign nature. 

Laura Trinke - Mulcahy Human Chromosomes at 3 Stages of Mitosis

Recessive genes and carrier status

Human cells carry two copies of each chromosome - so they have two versions which are called alleles. Alleles  can be either dominant or recessive. 

Dominant alleles show their effect even if the individual has only one copy of the allele - also known as being heterozygous. 

Recessive alleles only show their effect if the individual has two copies of that allele, known as being homozygous. For example, the allele for blue eyes is recessive, so to have blue eyes you need to have both copies of the blue eye allele. A hereditary carrier is a person who has a recessive allele but as they only have one and not a pair of recessive genes, they do not express that trait. 

We test for some carrier recessive genes such as cystic fibrosis. If both parents have the Cystic Fibrosis gene alteration, there is a one in four chance a child will have both copies of the gene alteration, one from each parent and therefore have the condition.

What other techniques are involved in Whole Genome sequencing that will help patients? 

Polygenic Risk Scores are able to be done as part of research for all participants.

This is a technique for finding participants who have an increased risk of certain conditions. Single nucleotide polymorphisms (SNPs) are spelling mistakes in the genetic code, usually found outside genes. While the presence of an individual SNP may only cause a very small increased risk for a particular condition – for example prostate cancer, they can be combined to add up to a large risk.

If one looks for 170 SNPs known to increase the risk of prostate cancer, we will be able to find people who have five times the risk of the normal population. Polygenic risk scores are calculated by adding up all the individual SNPs.

Polygenic risk scores are a major gain of doing Whole Genome screening. This cannot be done by “whole exome screening” – which only looks at the genes themselves. Nor by “panel tests” – where just a specific group of cancer genes are investigated.

This is why Whole Genome screening is the “holy grail” of genetics.