In a milestone for rare diseases, exome sequencing and microarray analyses delivered a diagnosis for 41% of children with severe developmental disorders in a large-scale study conducted by researchers in the United Kingdom and Ireland. Around three-quarters of the conditions diagnosed were caused by spontaneous mutations not inherited from either parent
The study was published this week in the New England Journal of Medicine. Caroline F. Wright, PhD, of the University of Exeter, is the lead author.
More than 13,500 families from 24 regional genetics services across the U.K. and Ireland were recruited to the study, a collaboration between the NHS and the Wellcome Sanger Institute.
All the children had a severe developmental disorder that was previously undiagnosed. The Wellcome Sanger Institute sequenced all the genes in the children’s and parents’ genomes.
The researchers noted that many of these diagnoses were only made possible by combining data across all diagnostic centers in the U.K. and Ireland. A similar approach to diagnosing individuals with rare diseases is now being used by the NHS Genomic Medicine Service.
The research team also found that the chances of success in getting a diagnosis were highest in families of European ancestry, reinforcing the need to increase research participation for under-represented groups.
An accompanying NEJM editorial (Posey, J and Lupski) noted: “The field of clinical genomics has been particularly challenged by the continuous evolution of both knowledge (e.g., the steady pace of new disease gene discoveries) and molecular diagnostic techniques. ‘Best practices’ have often been more readily defined according to the requirements of health care systems and payers rather than the findings from any true, broad assessment of diagnostic utility.”
The study incorporates the team’s 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.
Helen Firth, senior co-author and clinical lead of the study said, “Embedding a powerful informatics platform at the heart of this study facilitated the collaboration with families, clinicians, and scientists engaged in the project, and played a crucial role in its diagnostic success and in the discovery and ultimately treatment of new causes of rare genomic disease.” Firth is honorary professor of clinical genomics at Cambridge University Hospitals NHS Foundation Trust.
The editorialists added: “Recruitment in a family trio (proband plus biologic parents) had the greatest effect on increasing the chance of receiving a molecular diagnosis. Other factors that increased the chance were the presence of severe intellectual or developmental disability, a greater number of organ systems affected, the presence of features suggestive of a syndrome, and having only one affected family member.”
In addition to making thousands of new diagnoses for patients, the authors noted that the study has so far resulted in more than 290 publications, identified approximately 60 new disorders, and enabled more than 350 genotype, or phenotype-specific projects, led by clinicians and researchers across all 24 recruitment sites.
