A series of groundbreaking studies, published today, could help to improve efforts to identify clinically relevant genetic variation for human disease.

Scientists from the MRC Clinical Sciences Centre have been involved in two of the three studies. The first, an in-depth analysis of the exomes (protein-coding regions) of the human genome, provides the most comprehensive catalogue of genetic variation in these regions to date, according to the editorial team at Nature, where the research is published.

The CSC’s Chain Florey clinical lecturer Dr James Ware is an author on this ExAC paper and also on a separate paper published today in Genomics In Medicine, for which the CSC’s Professor Stuart Cook is a senior author. In this second paper, Roddy Walsh of imperial College London, Stuart Cook of the MRC CSC, Hugh Watkins of the University of Oxford and colleagues evaluated genetic variation in one of the most common serious Mendelian disorders, cardiomyopathy (disease of the heart muscle). Their findings suggest that many genes and variants previously associated with a given cardiomyopathy are likely spurious, but that variant interpretation can now be significantly improved using ExAC.

Professor Cook, who is also director of genetics at Royal Brompton & Harefield NHS Foundation Trust and Tanoto Foundation professor of cardiovascular medicine at the SingHealth Duke-NUS Academic Medical Centre in Singapore, said:

“For the first time, we can really look at what is important and what is not. This helps us pinpoint the variants that are causing the disease and identify parts of protein that are hotspots for the mutations. When we can be firmer in our diagnosis we no longer have to carry out follow-up tests for those who don’t need it.”

The Nature paper comes from the Exome Aggregation Consortium (ExAC). Daniel MacArthur and colleagues sequenced the exomes of 60,706 individuals of diverse geographic ancestry, including European, African, South Asian, East Asian and Latino populations. They identified around 7.4 million genetic variants, providing unprecedented resolution into low-frequency protein-coding variants in human populations. The authors analyse this dataset to characterize patterns of genetic variation worldwide, bringing resolution that has not been possible on smaller datasets of genetic variation. The density of genetic variation has allowed for resolution of multiple sequence variants at the same site (multiallelic variants), while the size of the dataset allows some of the first findings on mutational recurrence — rare mutations arising independently during the history of the populations.

ExAC provides an openly accessible reference database that has already proved useful as a clinical tool for evaluating purported Mendelian (single-gene) disease-causing variants, some of which are implausibly common in the population. The authors analysed 192 such variants reported in prior studies and found that only nine had sufficient data to support disease association.

In a third paper, also published today in Nature Genetics, Douglas Ruderfer of the Icahn School of Medicine at Mount Sinai, New York and colleagues analyse rare copy number variation (a type of genome structural variation) within the ExAC dataset.

For further information on the Genetics in Medicine paper on which professor Cook is a senior author, see below:

Improved analysis of genetic testing could lead to more patients with inherited conditions being successfully diagnosed 

A groundbreaking study, led by experts from Royal Brompton Hospital and the University of Oxford, has discovered better methods to interpret the significance of gene mutations in patients who are tested for genetic conditions. The findings mean that, in future, more diagnoses could be made through genetic testing.

Researchers compared genetic data from nearly 8,000 patients who have the heart condition cardiomyopathy, with more than 60,000 reference samples from the general population. The aim was to reassess the role that variants in different genes play in causing the condition, which is a disease of the heart muscle that reduces its ability to pump blood around the body.

The cardiomyopathy data set, from the Oxford Molecular Genetics Laboratory and the Laboratory of Molecular Medicine, Partners HealthCare in Boston, USA, is the biggest ever analysed. Researchers compared this with a large volume of raw genetic data from the general population, available from a new database known as ExAC, which was compiled by an international consortium led by the MacArthur Lab in the USA.

Rare variants in genes that are typically associated with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC), were examined.

The results, published today in the journal Genetics in Medicine, found that rare variants in some of these genes were not any more common in the cardiomyopathy patients than the general population. This shows they are unlikely to be valid disease-causing genes and that having rare gene variants is collectively more common than previously thought.

The analysis found that only eight out of 48 genes previously implicated in DCM, and two thirds of genes that are regularly screened for HCM, were found to be much more common among the cardiomyopathy patients. This means they are more likely to be disease-causing and therefore most relevant for genetic testing. As a result, clinical scientists can take a more targeted approach and have increased confidence to provide a positive diagnosis if one of these gene variants is found. In the past clinical labs may have taken a more conservative approach, meaning that patients might have received an inconclusive result.

Cardiomyopathies are diseases of the heart muscle, which affect around 1 in 500 people in the UK. The condition causes the heart to stop pumping blood as efficiently as it should, which can lead to heart failure or an irregular heartbeat. Symptoms include breathlessness, chest pain, palpitations, dizziness and loss of consciousness. Cardiomyopathies are the most common cause of sudden death in otherwise healthy young people.

Relatives of cardiomyopathy patients often undergo heart tests because the condition can be genetic. Those found to have no symptoms may have a genetic test to confirm they have the same gene variant as their family member, meaning they can be monitored and treated, often before the condition can be detected on conventional tests. Those who do not have the faulty gene can be reassured and avoid long-term follow-up, saving the NHS money. Currently, if genetic testing is inconclusive, relatives usually receive life-long care in case they later develop the condition. It is hoped the new research findings will lead to an increase in the number of conclusive diagnoses.

Researcher Roddy Walsh, from the NIHR Royal Brompton Cardiovascular Biomedical Research Unit, is a lead author of the paper. He said:

“This study has major implications for other diseases with strong genetic components as researchers can apply the same techniques to other studies using the ExAC database. The huge reference data set gives us an unprecedented understanding of gene variation in a normal population, while the large collection of data from cardiomyopathy patients has allowed us to make new insights into the disease.

“Overall, the database has found higher levels of gene variants in the general population than previously thought, but many of these do not cause disease. So it is about knowing what is significant and what isn’t, and communicating that to clinicians so they know how best to interpret genetic tests.”

Professor Hugh Watkins, head of the Radcliffe Department of Medicine at the University of Oxford and one of the senior authors of the paper, said:

“These results will help diagnostic laboratories avoid testing genes that can’t be interpreted reliably and be more confident in interpreting variants in the genes that we have shown to be valid.”

Professor Stuart Cook, director of genetics at Royal Brompton & Harefield NHS Foundation Trust and Tanoto Foundation professor of cardiovascular medicine at the SingHealth Duke-NUS Academic Medical Centre in Singapore, is another senior author. He said:

“For the first time, we can really look at what is important and what is not. This helps us pinpoint the variants that are causing the disease and identify parts of protein that are hotspots for the mutations. When we can be firmer in our diagnosis we no longer have to carry out follow-up tests for those who don’t need it.”

The research was supported by the NIHR Royal Brompton Cardiovascular Biomedical Research Unit and Imperial College London, NIHR Oxford Biomedical Research Centre, the British Heart Foundation, Wellcome Trust, Fondation Leducq, Medical Research Council, Academy of Medical Sciences and National Medical Research Council (NMRC) Singapore.

Read more about today’s publications here and here.