A new academic paper has revealed that areas of the human genome that are routinely overlooked in clinical tests may be the cause of some rare diseases.
Assessing 122 patients with genetic conditions including rare forms of heart arrhythmia, brain inflammation, inflammatory bowel disease and kidney abnormalities, the study looked at areas of the genome often considered to be ‘junk DNA’ because it does not relate to the production of proteins.
Variants involving this non-coding DNA were found to be a factor in a number of patients. Five genes that are novel, or were novel at the time of discovery, were identified, whilst another three genes were suspected of causing rare medical conditions.
As a result of the study, clinical diagnoses were changed in six patients and treatments were adjusted for eight. For five of these patients this intervention was considered to be lifesaving. The research also led to the development of UK guidelines on the use of genomics in the NHS, informed by contributions from patients enrolled in this study.
The paper presented the findings of a major project led by researchers at the University of Oxford’s Centre for Human Genetics supported by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC). The study, published in the journal Genomic Medicine, and presented at the American Society of Human Genetics’ annual meeting in Washington DC in November 2023, was funded by the Wellcome Trust and Department of Health and Social Care as part of the Health Innovation Challenge Fund.
DNA contains code – or instructions – used to make proteins in the cell. But in the human genome, the vast majority of DNA is non-coding.
Much of the research into the genetic causes of rare diseases has focused on exome sequencing; that is, the regions of DNA that are turned into proteins. This approach also often misses structural variants, a type of error involving the deletion, insertion or mis-orientation of chunks of DNA across coding and non-coding DNA regions. This study has demonstrated that large parts of the genome that are routinely overlooked do in fact play a role in rare diseases.
Professor Jenny Taylor, who led the study, said: “Genome sequencing has become an important first-line genetic test for many rare diseases in routine clinical settings and can make a substantial contribution to rapidly identifying a cause for many patients’ conditions, shortening their diagnostic odyssey.
“This research has demonstrated the need to analyse the entire genome – not just the exomes that code for proteins – to maximise the value of clinical genome sequencing. We have found that structural, splice site and regulatory DNA variants involving intronic and inter-genic regions can make a significant contribution to diagnostic yield.”
The paper is a product of a study that began in 2015 to evaluate the clinical usefulness of whole genome sequencing across a number of human diseases, which succeeded in identifying several new genes responsible for rare conditions, leading to improved diagnostic tests for inherited diseases in the NHS. It also led to the development of UK guidelines on the use of genomics in the NHS, informed by contributions from patients enrolled in this study.
Professor Taylor’s team’s analysis included the often-neglected introns – the non-coding sequences present in the DNA – which are removed when exons are spliced together in the process that leads to the creation of proteins.
“People have focused a lot on the single nucleotide variants, which are like typos – single letters that change the meaning of a word. But you can sometimes get words that are deleted that change the meaning of a sentence or you can get a whole paragraph that’s deleted – what we call structural variants,” Professor Taylor, who is Co-theme Lead of the Oxford BRC’s Genomic Medicine Theme, said.
“We believe we are missing a lot of diagnoses because we are not focusing enough on variants in these intronic and inter-genic regions. This paper emphasises how, if we consider the structural splice-site and regulatory variants in these regions, we can give more patients and their families the diagnoses they are looking for.