A major nationwide study has given answers to around 5500 children with severe developmental disorders as to the genetic cause of their condition. The study will "help improve diagnosis" across the world, said researchers.
The authors of the new study, published in the New England Journal of Medicine, pointed out that paediatric disorders included a range of highly penetrant, genetically heterogeneous conditions amenable to genome-wide diagnostic approaches. "Finding a molecular diagnosis is challenging but can have profound lifelong benefits," they surged.
Professor Caroline Wright, professor of genomic medicine at Exeter University and lead author, said: "Getting the right diagnosis is absolutely critical for families with rare conditions, which collectively affect around 1 in 17 people. Most of these conditions are genetic and can be diagnosed using the same genomic sequencing technology."
"Extraordinary strides" had been made toward identifying novel molecular causes for rare monogenic disorders due to genomic sequencing, the authors said, particularly in paediatrics. This was partly because of the high clinical need and potential for lifelong benefit with diagnosis and treatment, plus the early presentation of a patient with severe disease made genetic diagnosis "more feasible" since causal variants were largely absent from control data sets, they explained.
Data Sharing 'Critical' For Making Diagnoses
One of the first studies to combine large-scale genomic research with individual patient feedback was the Deciphering Developmental Disorders (DDD) study, which recruited more than 13,500 families and generated exome sequencing and microarray data.
For their randomised controlled clinical trial, the researchers conducted a large-scale sequencing study involving families with probands with "severe, probably monogenic, difficult-to-diagnose" developmental disorders, from 24 regional genetics services in the UK and Ireland. They utilised analytic strategies developed over a decade in the DDD study to identify and classify thousands of new molecular diagnoses and report the factors affecting the probability of receiving a diagnosis.
Getting the right diagnosis can guide clinical care, bring together families in support networks, and reduce the "isolation" of having a child with an ultra-rare condition, the authors underlined.
Senior co-author Professor Matthew Hurles, incoming director of the Wellcome Sanger Institute and honorary professor of human genetics and genomics, University of Cambridge, and senior co-author, said that responsible data sharing was "critical" for making the diagnoses. He emphasised that 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".
Professor Helen Firth, consultant clinical geneticist at Cambridge University Hospitals, and senior co-author and lead clinician for the study, emphasised the importance of the DECIPHER informatics platform for supporting recruitment of patients and return of diagnostic findings to clinical teams. She stressed that "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".
Families Desperate For Answers
All the families in the study had children with a severe developmental disorder, which was undiagnosed despite prior testing, and likely to be caused by a single genetic change, the authors said.
The researchers collected standardised phenotypic data, and performed exome sequencing and microarray analyses to investigate novel genetic causes. They developed an "iterative variant analysis pipeline" and reported candidate variants to clinical teams for "validation and diagnostic interpretation" to inform communication with families.
A total of 13,449 probands were included in the analyses. A diagnosis was made in approximately 41% of probands (5502 of 13,449), of whom 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders.
Probands were less likely to receive a diagnosis if they were born extremely prematurely (22 to 27 weeks' gestation; odds ratio 0.39), had in utero exposure to antiepileptic medications (odds ratio 0.44), had mothers with diabetes (odds ratio 0.52), or were of African ancestry (odds ratio 0.51).
The team said that, so far, they had been able to provide genetic diagnoses for "around 5500 children" in the study, and that the diagnoses were in "over 800 different genes", including "60 new conditions" previously discovered by the study. Around three-quarters of the conditions were caused by spontaneous mutations not inherited from either parent, they highlighted.
The research team also found that the chances of success in getting a diagnosis was lower in families of non-European ancestry, which they pointed out reinforced the "imperative" to increase research participation for under-represented groups.
"Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genome-wide data had good diagnostic power, even after previous attempts at diagnosis," the authors enthused.
Professor Hurles highlighted how many of the diagnoses were only made possible through combining data across all diagnostic centres in the UK and Ireland. "For some diagnoses, it was only through sharing data with international colleagues that it was possible to make a diagnosis," he underlined. "As these genomic technologies move into routine healthcare, ensuring that undiagnosed patients can still benefit from research on their data will remain incredibly important," he cogitated.
"The families in our study were desperate for answers, which can make a huge difference to clinical management and quality of life," Professor Wright reiterated. By sharing the findings of the study, she believed that "many more families in the future should get answers faster".