Zemojtel, Tomasz, koehler, Sebastian, Mackenroth, Luisa, Jaeger, Marten, Hecht, Jochen, Krawitz, Peter, Graul-Neumann, Luitgard, Doelken, Sandra, Ehmke, Nadja, Spielmann, Malte ORCID: 0000-0002-0583-4683, Oien, Nancy Christine, Schweiger, Michal R., Krueger, Ulrike, Frommer, Goetz, Fischer, Bjoern, Kornak, Uwe, Floettmann, Ricarda, Ardeshirdavani, Amin ORCID: 0000-0002-7226-7324, Moreau, Yves, Lewis, Suzanna E., Haendel, Melissa, Smedley, Damian, Horn, Denise, Mundlos, Stefan and Robinson, Peter N. (2014). Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome. Sci. Transl. Med., 6 (252). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1946-6242

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Abstract

Less than half of patients with suspected genetic disease receive a molecular diagnosis. We have therefore integrated next-generation sequencing (NGS), bioinformatics, and clinical data into an effective diagnostic work-flow. We used variants in the 2741 established Mendelian disease genes [the disease-associated genome (DAG)] to develop a targeted enrichment DAG panel (7.1 Mb), which achieves a coverage of 20-fold or better for 98% of bases. Furthermore, we established a computational method [Phenotypic Interpretation of eXomes (PhenIX)] that evaluated and ranked variants based on pathogenicity and semantic similarity of patients' phenotype described by Human Phenotype Ontology (HPO) terms to those of 3991 Mendelian diseases. In computer simulations, ranking genes based on the variant score put the true gene in first place less than 5% of the time; PhenIX placed the correct gene in first place more than 86% of the time. In a retrospective test of PhenIX on 52 patients with previously identified mutations and known diagnoses, the correct gene achieved a mean rank of 2.1. In a prospective study on 40 individuals without a diagnosis, PhenIX analysis enabled a diagnosis in 11 cases (28%, at a mean rank of 2.4). Thus, the NGS of the DAG followed by phenotype-driven bioinformatic analysis allows quick and effective differential diagnostics in medical genetics.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Zemojtel, TomaszUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
koehler, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mackenroth, LuisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jaeger, MartenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hecht, JochenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krawitz, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Graul-Neumann, LuitgardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doelken, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ehmke, NadjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spielmann, MalteUNSPECIFIEDorcid.org/0000-0002-0583-4683UNSPECIFIED
Oien, Nancy ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schweiger, Michal R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frommer, GoetzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, BjoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kornak, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Floettmann, RicardaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ardeshirdavani, AminUNSPECIFIEDorcid.org/0000-0002-7226-7324UNSPECIFIED
Moreau, YvesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lewis, Suzanna E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haendel, MelissaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smedley, DamianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horn, DeniseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mundlos, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robinson, Peter N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-428987
DOI: 10.1126/scitranslmed.3009262
Journal or Publication Title: Sci. Transl. Med.
Volume: 6
Number: 252
Date: 2014
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication: WASHINGTON
ISSN: 1946-6242
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MUCOLIPIDOSIS TYPE-IV; INTELLECTUAL DISABILITY; MISSENSE MUTATIONS; ALKALINE-PHOSPHATASE; MENTAL-RETARDATION; DATABASE; HYPOPHOSPHATASIA; DISORDERS; VARIANTS; ONTOLOGYMultiple languages
Cell Biology; Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/42898

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