Summary of a genetics-related, primary article in a peer-reviewed journal

The primary article, Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland published in the peer-reviewed New England Journal of Medicine identifies challenges that arise when attempting to find a molecular diagnosis for rare pediatric diseases, however, there are profound benefits and advantages for affected individuals and their loved ones. The study involves many participants, with more than 13,500 families with difficult-to-diagnose, severe, monogenic (caused by a single gene), developmental disorders that were receiving genetic services in the United Kingdom and Ireland.

A total number of 13,449 individuals with severe developmental disorders were included in the research methods. On initial analysis, 41% of the individuals tested received a diagnosis based solely on clinical and computational approaches. Among these participants, specifically, those receiving a diagnosis based on clinical hypothesis, 76% of the participants were found to display features that had a pathogenic de novo variant. Another 22% of the individuals with severe developmental disorders were found to have variants associated with single-gene developmental disorders. Another factor that highly influenced the probability of a diagnosis was the use of family-based association studies, like parent-offspring trios. The methods of the study explained that by using the genetic information of the parents, there was an increased probability of receiving a diagnosis with a high confidence interval. On the other hand, participants without a complete trio, those born prematurely, those with in-utero exposure to anticonvulsant medications, mothers with diabetes, or those of African ancestry were found to be less likely to receive a diagnosis due to a lack of ancestry-matched control.

The article then describes the importance of the pioneering work in the Deciphering Developmental Disorders (DDD) study, where there were several combined efforts to collect data and perform genomic sequencing to identify several thousands of new molecular diseases. The DDD study explains the factors which influence the probability of receiving a diagnosis and the importance of focusing on pediatrics due to the lifelong benefits of receiving early treatment. In the study, more than half of the participants from regions in the United Kingdom and Ireland were recruited in parent-offspring trios with previously undiagnosed developmental disorders. Throughout the study, many ethical considerations were discussed and addressed with participants. These considerations include building and maintaining partnerships at the clinical research interface, recruitment, consent, capacity and eligibility, sample inclusion, collection, and verification, sharing clinically relevant variants, sharing genome-wide variants, and managing withdrawal.

The Deciphering Developmental Disorders study demonstrates the value of analysis and improving methods used to diagnose developmental disorders while also focusing on the challenges for those less likely to receive an early diagnosis. Identification and diagnosis of these diseases depend on several factors, such as other gene associations, evaluations of incomplete variants, and interpretation of data. A program named DECIPHER allowed for enhanced diagnostic advances to re-evaluate current data in the known database each time a patient is assessed, allowing for the growth of information with each diagnosis. Although the study did not have information on every genetic variant for a developmental disorder, the DDD study approach played an enormous role in making significant advances in gathering and improving collection methods to improve genetic data interpretation with each diagnosis.

References

Wright, C.F. et al. Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland. The New England Journal of Medicine 388, 1559-1571 (2023).