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

Autor: Zhu X; Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA., Petrovski S; Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.; Department of Medicine, University of Melbourne, Austin Health and Royal Melbourne Hospital, Melbourne, Australia., Xie P; Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.; Present address: Department of Human Genetics, McGill University, Montreal, Quebec, Canada., Ruzzo EK; Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA., Lu YF; Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA., McSweeney KM; Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA., Ben-Zeev B; Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Nissenkorn A; Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Anikster Y; Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Oz-Levi D; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel., Dhindsa RS; Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA., Hitomi Y; Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.; Present address: Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan., Schoch K; Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA., Spillmann RC; Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA., Heimer G; Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.; Pinchas Borenstein Talpiot Medical Leadership Program, Pediatric Neurology Unit, Chaim Sheba Medical Center, Tel HaShomer, Israel., Marek-Yagel D; Metabolic Disease Unit, Edmond and Lily Children's Hospital, Sheba Medical Center, Ramat Gan, Israel., Tzadok M; Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Han Y; Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA., Worley G; Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA., Goldstein J; Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA., Jiang YH; Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.; Department of Neurobiology, Duke University, Durham, North Carolina, USA., Lancet D; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel., Pras E; Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.; Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel., Shashi V; Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA., McHale D; UCB NewMedicines, Slough, UK., Need AC; Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.; Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK., Goldstein DB; Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.
Jazyk: angličtina
Zdroj: Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2015 Oct; Vol. 17 (10), pp. 774-81. Date of Electronic Publication: 2015 Jan 15.
DOI: 10.1038/gim.2014.191
Abstrakt: 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.
Databáze: MEDLINE
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