Large European study underlines power of genomic sequencing to diagnose diseases

LONDON — Using genome sequencing greatly expanded the number of diagnoses researchers could provide for children with developmental disorders from thousands of families across the United Kingdom and Ireland, researchers reported in a new study Wednesday.

The study, published in the New England Journal of Medicine, focused on children with severe developmental disorders who hadn’t received diagnoses through other standard methods. It further validates the power of genome sequencing to pinpoint the roots of rare diseases.

“We’ve been able to diagnose thousands of families who were living with these rare developmental disorders, but also we’ve been able to discover new genetic conditions that will ultimately make a huge difference to future generations,” said Caroline Wright, a professor of genomic medicine at the University of Exeter and the lead author of the study.

The paper describes results from the Deciphering Developmental Disorders project, which dates back more than a decade. The study recruited more than 13,000 families from 2011 to 2015, a time when emerging genomic tools were inspiring researchers to consider how to bring the technology to patients. The project aimed to combine a major research endeavor — one that would comb through thousands of genomes to identify new disease-causing mutations — with a way to use those results to inform and improve individual patient care.

Throughout the project, researchers have been reporting their findings, leading to nearly 300 publications thus far. The new paper serves as a sweeping summary of the effort’s outcomes, with some 5,500 children receiving diagnoses of conditions caused by mutations on 800 different genes, and researchers identifying 60 new genetic conditions. The project involved patients at 24 regional genetics services from across the U.K. and Ireland, while experts at the Wellcome Sanger Institute conducted the sequencing.

In an editorial also published Wednesday, Jennifer Posey and James Lupski, two genetics experts at Baylor College of Medicine, called the DDD project “a remarkable study notable for its scale (>13,500 families …), scope (all branches of pediatric clinical practice), and implementation in clinical practice.”

The DDD project is just one of many initiatives that have demonstrated the potential of sequencing as a diagnostic tool. Whole genome sequencing is increasingly being used in clinical care as the cost of the technology has dropped and its speed has increased. (The DDD project relied on exome sequencing — reading the portion of the genome that encodes proteins — and other tools that look at segments of a person’s DNA.) The National Health Service, for example, started a genomic medicine service for patients in 2018, and last year, England launched a pilot program to sequence portions of DNA from 100,000 newborns as a test for wider sequencing at birth.

Even with the power of sequencing, researchers in the DDD project have yet to establish diagnoses for several thousand participants — a reminder that there are still innumerable genetic variants that scientists can’t say for certain are pathogenic (disease-causing) or benign. In some cases, researchers identified variants that seemed suspicious, but not enough was known about the specific version of the gene to verify it was the root of the child’s condition.

In the study, scientists were more likely to arrive at a diagnosis when they could analyze the DNA of the patient and both parents, because that allowed the researchers to pinpoint tiny changes in the genome between the generations that could cause the child’s condition.

The diagnostic rate was comparatively low, however, for children of African descent — another example of the problems caused by a lack of diversity in genomic databases, which are disproportionately made up of DNA from people of European ancestry.

To pinpoint which of the millions of genetic variants a person has is pathogenic, researchers compare that person’s variants to those in population databases. With people of European descent, researchers have information from enough genomes to more easily parse which genetic variants are rare and might be pathogenic, and which aren’t. With a child of African descent, researchers don’t have as many genomes to look to in order to characterize certain variants and figure out which one is the culprit.

For many children in the study, receiving a firm diagnosis didn’t change their clinical care; there are no treatments for many very rare conditions. But researchers say identifying the specific cause of a disease offers other benefits. Parents can better understand the risks of having another child with the condition, for example, and families of children with the same diagnosis can support each other and find resources.

“Having an answer is hugely important to that family,” Wright said.