HealthDay News – About 5% of patients for whom whole-exome sequencing is informative have multiple molecular diagnoses, according to research published online Dec. 7 in the New England Journal of Medicine.

Jennifer E. Posey, MD, PhD, from the Baylor College of Medicine in Houston, and colleagues conducted a retrospective analysis of data from 7,374 unrelated patients who had been referred for whole-exome sequencing. The authors examined the frequency and clinical characteristics for patients with more than one molecular diagnosis, and calculated the phenotypic similarity between molecularly diagnosed pairs of diseases.

The researchers found that 28.2% of patients had a molecular diagnosis; of these, 4.9 percent had diagnoses involving two or more disease loci. When available, parental samples were analyzed; de novo variants accounted for 67.8% and 51.7% of pathogenic variants in autosomal dominant and X-linked disease genes, respectively.

Continue Reading

 Among patients with two monoallelic variants, 44.7% had both variants de novo. Twelve patients with multiple diagnoses (11.9%) had causal copy-number variants. 

For patients in whom the phenotype resulted from two distinct mendelian disorders affecting different organ systems (50 patients), the phenotypic similarity score was significantly lower compared with patients with disorders that had overlapping features (30 patients; median score, 0.21 versus 0.36).

“Our data challenge the notion that a diagnostic investigation is necessarily complete after a single genetic diagnosis has been obtained,” the authors write.

Related Articles


Posey JE, Harel T, Pengfei L, et al. Resolution of disease phenotypes resulting from multilocus genomic variation. 2016 Dec 7. doi: 10.1056/NEJMoa1516767 [Epub ahead of print]