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Baylor-Led Study Delves Deeper Into Multiple Diagnoses from Clinical Exome Sequencing

NEW YORK (GenomeWeb) – Researchers from Baylor College of Medicine and elsewhere have provided new details on the multiple molecular diagnoses that are sometimes made by clinical exome sequencing.

In a report published in the New England Journal of Medicine yesterday, the team outlined diagnostic patterns present in clinical exome sequences for almost 7,400 unrelated individuals tested consecutively at Baylor's diagnostic laboratory. Across this cohort, successful molecular diagnoses were made in more than 28 percent of cases, with almost 5 percent of those diagnoses involving alterations at more than one disease locus.

"Our data challenge the notion that a diagnostic investigation is necessarily complete after a single genetic diagnosis has been obtained," senior author James Lupski, a molecular and human genetics and pediatrics researcher at Baylor College of Medicine, and his co-authors wrote. "The phenotype of a patient with two genetic diagnoses may be influenced by the extent to which the phenotype associated with each individual disease overlaps that of the other."

The latest results build on work that Sharon Plon, a molecular and human genetics and pediatric oncology researcher at Baylor, presented at the New York Genome Center earlier this year. At the time, Plon provided information on 1,400 individuals diagnosed by exome sequencing, including 74 individuals with mutations at two disease loci, half a dozen individuals with mutations at three disease-related loci, and two individuals with mutations at four suspicious sites.

In the published study, the Baylor College of Medicine-led team described results from a retrospective analysis of 7,374 individuals tested. The group included 345 affected individuals whose parents were tested as well.

Of the 2,076 individuals who were diagnosed by exome sequencing, the authors noted that 101 individuals — or 4.9 percent of those diagnosed — had disease-related variants at two or more loci. In particular, two molecular diagnoses were made in 97 individuals, while three individuals had three molecular diagnoses, and four diagnoses were made in one individual.

By folding in parental sequence data, when possible, the researchers estimated that almost 68 percent of the autosomal dominant disease gene mutations appeared de novo in the affected individuals, rather than being inherited. Likewise, de novo variants appeared to account for nearly 52 percent of the X-linked disease gene changes identified. At least 20 diagnosed individuals carried homozygous mutations in autosomal recessive disease genes that were inherited from parents who each carried one mutated copy of the gene.

Their results also suggested that a significant proportion of the individuals with multiple disease-related gene alterations carried causal copy number changes: such changes were identified in 12 patients or 11.9 percent of those with multiple diagnoses.

Using information gleaned from the Online Mendelian Inheritance in Man and Human Phenotype Ontology databases, the team also attempted to establish a framework for distinguishing between cases with multiple molecular diagnoses that involved more than one distinct clinical phenotype and those with overlapping symptoms or phenotypes.

"Our results show that structured clinical ontologies can be used to determine the degree of overlap between two Mendelian diseases in the same patient; the diseases can be distinct or overlapping," the authors wrote. "Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway."