Editors' ChoiceHuman Genetics

Journey to the Center of the Cause

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Science Translational Medicine  07 Jan 2015:
Vol. 7, Issue 269, pp. 269ec4
DOI: 10.1126/scitranslmed.aaa3471

The “diagnostic odyssey” refers to myriad tests that an individual with an undiagnosed disorder can undergo before reaching—or not reaching—a diagnosis. It is not uncommon for children with developmental disorders such as developmental delays, intellectual disability, epilepsy, or autism spectrum disorder to undergo extensive testing in search of a genetic cause, which in most cases is not found. In children who do not have additional clinical features that point to a recognizable genetic syndrome, it is especially difficult to determine a priori the test that is most likely to provide an answer.

The introduction of genome-wide tests has begun to streamline the diagnostic process. Participants in the Deciphering Developmental Disorders (DDD) Study (www.ddduk.org) set out to determine the efficiency of using a combination of genome-wide copy-number and sequence analyses to diagnose children with developmental disorders. The study brings together clinicians and researchers across the United Kingdom, and to date, they have collected ~10,000 families with one or more affected individuals. In the current study, the authors report the results for the first 1133 children from 1101 families.

Combining data from whole-exome sequencing, genome-wide exon-focused array comparative genomic hybridization (CGH), and genome-wide genotyping, the researchers were able to identify a genetic cause in 28% of children. Importantly, they found evidence for 12 new genes that when mutated may cause developmental disorders, explaining another 3% of cases. For some genes, causative mutations were identified in multiple patients, but even the most frequently identified cause (mutation in ARID1B) was relevant to only ~1% of patients.

The DDD study is a well-coordinated effort involving a large number of clinical and diagnostic centers. The results of this study showed that comprehensive genomic testing early in the diagnostic process can be useful for patients and families. However, it also highlights the need for international collaborations and massive patient cohorts to pinpoint new genes and mutations that cause developmental disorders, as there are likely to be many genes, each of which explains a very small fraction of cases. Finally, new testing and analysis strategies may be required to provide a diagnosis for the 69% of cases still on the diagnostic odyssey.

The Deciphering Developmental Disorders Study, Large-scale discovery of novel genetic causes of developmental disorders. Nature 10.1038/nature14135 (2014). [Abstract]

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