Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.

2015-01-15

Zhu, Xiaolin

Petrovski, Slavé

Xie, Pingxing

Ruzzo, Elizabeth K

Lu, Yi-Fan

McSweeney, K Melodi

Ben-Zeev, Bruria

Nissenkorn, Andreea

Anikster, Yair

Oz-Levi, Danit

Dhindsa, Ryan S

Hitomi, Yuki

Schoch, Kelly

Spillmann, Rebecca C

Heimer, Gali

Marek-Yagel, Dina

Tzadok, Michal

Han, Yujun

Worley, Gordon

Goldstein, Jennifer

Jiang, Yong-Hui

Lancet, Doron

Pras, Elon

Shashi, Vandana

McHale, Duncan

Need, Anna C

Goldstein, David B

Journal Article

10.1038/gim.2014.191

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.Genet Med advance online publication 15 January 2015Genetics in Medicine (2015); doi:10.1038/gim.2014.191.

link

Genetics in Medicine : Official Journal of the American College of Medical Genetics 2015; 17(10): 774-81

Genetics in medicine : official journal of the American College of Medical Genetics