Elsevier

Genetics in Medicine

Volume 17, Issue 10, October 2015, Pages 774-781
Genetics in Medicine

Original Research Article
Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios

https://doi.org/10.1038/gim.2014.191Get rights and content
Under a Creative Commons license
open access

Abstract

Purpose

Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene–disease associations.

Methods

We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients.

Results

We obtained a genetic diagnosis for 29 (24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice (P = 3.4 × 10−8). This enrichment is only partially explained by mutations found in known disease-causing genes.

Conclusion

This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications.

Keywords

diagnosis
genic intolerance
HNRNPU
rare disease
whole-exome sequencing

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