Kidney disease: whole genome sequencing holds the key to cheaper, more accurate diagnosis

Research from Garvan and St Vincent’s Hospital has shown that whole genome sequencing has the potential to transform the diagnosis of a common inherited kidney disease.

Dr Amali Mallawaarachchi

04 November 2016

Whole genome sequencing (WGS) has the potential to transform clinical approaches to inherited kidney disease by making the diagnostic process cheaper and more accurate, says Dr Amali Mallawaarachchi, a genomics researcher at the Garvan Institute of Medical Research and a nephrologist at Sydney’s Liverpool Hospital.

Dr Mallawaarachchi was speaking yesterday to an audience of clinicians and researchers at the 2016 Renal Genetics Symposium, organized by KidGen, at the Royal Women’s Hospital, Melbourne.

Her talk focused on autosomal dominant polycystic kidney disease (ADPKD), an inherited disorder in which cysts progressively expand and destroy the kidneys, eventually causing renal failure.

The work she described was initiated when nephrologist Dr Tim Furlong from St Vincent’s Hospital approached Professor John Shine (at Garvan) about the need for Australians to get access to better genetic tests for inherited kidney disease. Close to 1 in 500 Australians are affected by this incurable disease, at an annual cost of about $80 million.

“ADPKD is usually caused by mutations in the PKD1 or PKD2 genes, although their function is not yet understood,” Dr Mallawaarachchi said.

“Unfortunately, single gene testing for ADPKD is unusually complicated and expensive because of the existence of 6 so-called ‘pseudogenes’ – non-functional genes that are almost identical to PKD1 and located right next to it on the genome.

“Because these pseudogenes are so similar to PKD1, traditional sequencing methods have great difficulty distinguishing them from the real PKD1 gene.

“So, our multidisciplinary team theorised that a WGS approach – in which all of an individual’s genes are sequenced – might improve diagnostic accuracy. And we’re delighted to report that it does.”

In a recent paper in the European Journal of Human Genetics, Dr Mallawaarachchi and colleagues at Garvan and St Vincent’s Hospital used WGS to accurately diagnose ADPKD in 86% of study participants – a substantial improvement on single-gene testing, which typically delivers an accurate result in only 60% of cases. This demonstrates the potential for a new diagnostic test, which has big implications for people with ADPKD.   

‘This research is really exciting, as previously it has been very difficult to sequence these genes so testing has been difficult to access,’ said Dr Mallawaarachchi.

The project is a close collaboration between Garvan and St Vincent’s Hospital, which sit on the same Research Precinct in Sydney’s Darlinghurst

The small research group includes Ms Yvonne Hort, Dr Mallawaarachchi and Dr Mark Cowley, Team Leader for Translational Genomics, and was enabled by technologies within Garvan’s Kinghorn Centre for Clinical Genomics (KCCG), the southern hemisphere’s largest genome sequencing centre.

‘This project is a great example of multidisciplinary research. Not one of the physicians or scientists could have accomplished this work on their own,’ said Dr Furlong.

The research team are now working to develop the WGS-based test for use in the clinic.

‘If we can diagnose it better, sooner, maybe we can intervene and prevent the full-blown renal failure,’ said Dr Cowley.


Why whole genome sequencing?

It may seem counterintuitive to use WGS, which sequences over 20,000 genes, to diagnose a disease caused by only two genes – yet WGS has compelling advantages over other forms of genetic testing.

Rather than targeting a specific gene, WGS provides a view of the whole genome. This means that WGS systems can more easily differentiate between PDK1 and its pseudogenes.

WGS can also provide a more complete picture. Some disease-causing mutations are located in areas that other types of genetic testing do not cover, such as splice regions and promoters.  

Apart from a cheaper and more accurate test, WGS could contribute to broader research about the function of the PKD1 and PKD2 genes. This is the first step towards developing targeted treatments.