RARE Daily

Genomics Study Provides Diagnoses to Thousands of Children with Rare Diseases

April 13, 2023

Rare Daily Staff

A study of 13,500 families across the United Kingdom and Ireland provided about 5,500 children with severe developmental disorders a genetic cause for their condition.

The results of the Deciphering Developmental Disorders (DDD) study, a collaboration between the NHS and the Wellcome Sanger Institute funded by Wellcome and the Department of Health and Social Care, and supported by the National Institute for Health and Care Research, is expected to improve diagnosis of rare diseases across the world. The results were published in the New England Journal of Medicine.

In an accompanying editorial, Jennifer Posey and James Lupski of Human Genome Sequencing Center at Baylor College of Medicine wrote that the findings from the study show how a genome-driven approach in combination with detailed clinical phenotyping improves the rate of diagnoses over the previous standard of care.

“Their study also emphasizes the important role of clinicians and clinical acumen, both on the front end of the physician–patient relationship (in phenotyping) and on the back end (in interpreting whether the implicated variant was indeed pathogenic and in determining the clinical relevance of findings to individual patients and their families),” the two wrote. “Although much work remains to be done in improving genomic diagnostics and in understanding disease biology, it is clear that clinical genomics in medical practice is making a difference for patients with rare genetic disorders and their families and physicians.”

All the families that participated in the study had children with a severe developmental disorder, which was undiagnosed despite prior testing through their national health service and likely to be caused by a single genetic change. The Wellcome Sanger Institute sequenced all the genes in the children’s and parents’ genomes to look for answers, a search which is still ongoing.

The diagnoses made to date were in more than 800 different genes, including 60 new conditions previously discovered by the study. One notable result was that around three-quarters of the conditions were caused by spontaneous mutations not inherited from either parent.

The research team also found that the chances of success in getting a diagnosis was lower in families of non-European ancestry, reinforcing the imperative to increase research participation for under-represented groups.

“Most of these conditions are genetic and can be diagnosed using the same genomic sequencing technology,” said Caroline Wright, professor of genomic medicine at the University of Exeter and lead author on the study. “The families in our study were desperate for answers, which can make a huge difference to clinical management and quality of life. We worked with hundreds of clinicians and scientists, as well as thousands of patients to try to find those answers. By sharing our findings, many more families in the future should get answers faster.”

A key part of the study is the DECIPHER informatics platform. This contains data from thousands of patients who have given consent for broad data-sharing enabling the information to be used, and built on, by an international community of academics and clinicians focused on genetics and rare disease genomics. That data sharing, according to study co-author Matthew Hurles, incoming director of the Wellcome Sanger Institute, played a critical role in enabling diagnoses.

“Undiagnosed patients with rare genetic diseases have the most to lose if they are not given an opportunity to participate in research and if their data are kept in silos. Many of these diagnoses were only made possible through combining data across all diagnostic centers in the U.K. and Ireland,” he said. “For some diagnoses, it was only through sharing data with international colleagues that it was possible to make a diagnosis. As these genomic technologies move into routine healthcare, ensuring that undiagnosed patients can still benefit from research on their data will remain incredibly important.”


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