ESPEYB20 12. The Year in Science and Medicine Genetics (5 abstracts)
12.2. Genomic diagnosis of rare pediatric disease in the United Kingdom and Ireland
Wright CF , Campbell P , Eberhardt RY , Aitken S , Perrett D , Brent S , Danecek P , Gardner EJ , Chundru VK , Lindsay SJ , Andrews K , Hampstead J , Kaplanis J , Samocha KE , Middleton A , Foreman J , Hobson RJ , Parker MJ , Martin HC , Fitz Patrick DR , Hurles ME & Firth HV for the DDD Study
N Engl J Med 2023 Vol. 388 Issue 17 Pages 1559–1571. DOI: 10.1056/NEJMoa2209046
Brief summary: In this large-scale, multicenter DNA sequencing study, probands (and families; n=13 449) with previously undiagnosed, severe, likely monogenic, complex developmental disorders from 24 centers in the UK and Irland were studied by whole exome sequencing and microarray analysis. Multimodal data analysis yielded a diagnosis in 41%, more likely with TRIO family analysis. Probands with a history of extreme prematurity, in utero exposure to antiepileptics and maternal diabetes as well as of African descent were less likely to have a genetic diagnosis identified.
In the field of rare diseases, genome sequencing is instrumental to identify a large number of underlying monogenic molecular causes. High throughput methods, decreasing prices and thus larger availability has given an additional spark to the field. This study shows that a genome approach combined with detailed phenotyping and sophisticated data analysis, integrating both genetic and clinical data and using an iterative analysis approach, can improve the diagnostic yield remarkably.
The study also points to well-known environmental factors that were identified in probands who remained without a genetic diagnosis. In the Discussion the authors suggest correctly that in such patients, gene variants of less severe effect size, but nevertheless contributing to the phenotype, might have been missed as this all depends on the data analysis plan.
Overall, not only developmental disorders but also other disorders, such as differences of sex development, have a heterogenous genetic architecture. In these groups of disorders, the discovery of underlying large burden, highly penetrant de novo variants is easier, while in the remaining individuals rare and common incompletely penetrant variants and nongenetic causes may contribute to the disease and are much more difficult to identify.
Note: This paper was published with an Editorial (1).
Reference: 1. Genomics in clinical practice. Jennifer E. Posey and James R. Lupski. N Engl J Med 388;17 April 27, 2023. DOI: 10.1056/NEJMe2302643.
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ESPE Yearbook of Paediatric Endocrinology
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