Whole genomic sequencing is viewed by many in the rare disease community as the holy grail for getting diagnosis. But a new study published in the New England Journal of Medicine
questions the ability of whole genome sequencing to be the best means to diagnose patients.
In the study, Posey et al performed a retrospective analysis of 7374 patients who had whole-exome sequencing performed. Whole-exome sequencing for cancer exome analysis was not included.
Among the 7374 samples, a molecular diagnosis was only found in 2076 patients (28.2%) but the most controversial observation found in the study was that only 101 patients (4.9%) had 2 or more molecular diagnoses. This value is much smaller than found using appropriate models (14.0% and 26.4%).
As many in the rare disease community are aware, multiple conditions are believed to be fairly common. The study by Posey et al would argue that those multiple conditions may actually be genetically linked.
With that said, the study has a major caveat to explain the low percentage of patients with multiple diagnoses. Approximately 70% of patients in this study did not get a diagnosis. Given that many of 7000 rare diseases are not fully understood, it is very likely that many diseases using whole-genome sequencing were not recognized.
The authors noted that their data “indicate that bioinformatic tools and a structured ontology may be used to objectively assess complex phenotypes and that overlapping phenotypes may involve protein pairs that interact closely at the molecular level (for example, ARID1B and ANKRD11) or more distantly at the level of a functional unit or organ system, such as the eye (CRYGD and COL4A1) or brain (PLA2G6 and BCAP31).”
Posey JE, Harel T, Liu P, et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. New Engl J Med.
Published online ahead Dec 7, 2016. DOI: 10.1056/NEJMoa1516767
Boycott KM, Innes M. When One Diagnosis is not enough. New Engl J Med.
Published online ahead Dec 7, 2016 10.1056/NEJMe1614384