Interpretation of Genomic Copy Number Variants Using DECIPHER
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- Abstract
- Table of Contents
- Figures
- Literature Cited
Abstract
Many patients suffering from developmental disorders have submicroscopic deletions or duplications affecting the copy number of dosage?sensitive genes or disrupting normal gene expression. Many of these changes are novel or extremely rare, making clinical interpretation problematic and genotype/phenotype correlations difficult. Identification of patients sharing a genomic rearrangement and having phenotypes in common increases certainty in the diagnosis and allows characterization of new syndromes. The DECIPHER database is an online repository of genotype and phenotype data whose chief objective is to facilitate the association of genomic variation with phenotype to enable the clinical interpretation of copy number variation (CNV). This unit shows how DECIPHER can be used to (1) search for consented patients sharing a defined chromosomal location, (2) navigate regions of interest using in?house visualization tools and the Ensembl genome browser, (3) analyze affected genes and prioritize them according to their likelihood of haploinsufficiency, (4) upload patient aberrations and phenotypes, and (5) create printouts at different levels of detail. By following this protocol, clinicians and researchers alike will be able to learn how to characterize their patients' chromosomal imbalances using DECIPHER. Curr. Protoc. Hum. Genet. 72:8.14.1?8.14.17 © 2012 by John Wiley & Sons, Inc.
Keywords: copy number variation; clinical genetics; array CGH; genotype; phenotype; developmental disorders; bioinformatics
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PDF or HTML at Wiley Online LibraryTable of Contents
- Introduction
- Basic Protocol 1: Searching DECIPHER by Location as a Public User
- Basic Protocol 2: Searching DECIPHER for a Phenotype as a Public User
- Basic Protocol 3: Adding a Patient to DECIPHER as a Registered Member
- Commentary
- Literature Cited
- Figures
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Figure 8.14.1 Vertical tabs on DECIPHER homepage show by default an interactive map with the location of all members of the consortium. View Image -
Figure 8.14.2 DECIPHER search box. This input box is visible on every page of DECIPHER's interface. Public users can search by phenotype, chromosomal location, gene name, or band. View Image -
Figure 8.14.3 Results retrieved from searching DECIPHER by location. The typed location was 5:85030173‐89050512 and 11 consented patients and no syndromes are found to overlap with region. View Image -
Figure 8.14.4 Click on Configure this page to add the DECIPHER track to Ensembl. View Image -
Figure 8.14.5 Interface in Ensembl to add the DECIPHER source. In the top right corner, type “DECIPHER” and immediately the DECIPHER data source appears. Click on the empty checkbox and a pop‐up window appears. Click on Normal and the click on the top right tick to save your configuration. View Image -
Figure 8.14.6 DECIPHER track as shown in Ensembl for the 5:85030173‐89050512 region. Red and blue correspond to losses and gains, respectively. Any bar in the Ensembl track contains links back to their DECIPHER entry. Only consented patient data are displayed. In this example, the feature bar for DECIPHER patient 135 is clicked and shows a pop‐up window with more detailed information about the aberration and a link back to the DECIPHER database. View Image -
Figure 8.14.7 Typical patient report. A series of tabs are provided describing the deposited information for this patient in DECIPHER. The top tabs refer to the patient and the second level tabs refer to each aberration. Each patient has an Overview, Aberration, Phenotypes, Citations, and Karyotype tab. Each aberration contains a graph, a list of HGNC genes, OMIM genes, OMIM morbid genes, Patient overlap, and a Syndrome overlap tab. View Image -
Figure 8.14.8 A total of ten genes have been found to be contained in the deleted region for patient 135. Genes are ordered according to their haploinsufficiency score (%HI). Those with no score come first and then the most likely to be haploinsufficient. The most haploinsufficient gene is predicted to be MEF2C. View Image -
Figure 8.14.9 GPR98, MEF2C, and RASA1 are identified as disease causing by OMIM Morbid among the list of overlapping genes in the 5:86170311‐90103610 region. View Image -
Figure 8.14.10 Search results for patients matching brachycephaly. A total of 79 consented patients have this phenotype. Any of these can be accessed for further inspection by clicking on the corresponding row. View Image -
Figure 8.14.11 Karyotype showing all regions affected for patients with the brachycephaly phenotype. A total number of 78 aberrations are displayed in the graph. Below it, a table shows all matched aberrations listed. A filter box is provided allowing further refinement of results. 5q14 was typed in the filter box, reducing the list to two aberrations. Clicking on any of these listed aberrations the user is redirected to its patient report. View Image -
Figure 8.14.12 Overlapping gains and losses for patient 249546. Losses are sorted in descending order by number of shared phenotypes. Note that shared phenotypes are highlighted in bold while the rest are in normal font. View Image -
Figure 8.14.13 My Patients tab after logging into DECIPHER shows all studies and patients available to the user. View Image -
Figure 8.14.14 Adding a patient requires first some overview information about the patient. Asterisks denote required fields. View Image -
Figure 8.14.15 Consent forms are required to be signed for sharing anonymized DECIPHER patient data. Forms are accessible via the Documents tab in the main menu and are available in several languages. View Image -
Figure 8.14.16 Pop‐up for adding an aberration. Asterisks denote required fields and only aberrations in GRCh37/hg19 are allowed. View Image -
Figure 8.14.17 Aberration tabs for a deletion in chromosome 12 starting at 64081319 and ending at 68947027. For this region, 28 genes are overlapped of which 16 are OMIM. Of these OMIM genes, 4 are denoted as Morbid. In total, 9 consented patients and syndromes overlap this aberration. View Image -
Figure 8.14.18 Overview information for 12q14 Microdeletion Syndrome. A synopsis of the clinical features, size of deletion, and expert advisor is provided, together with a link to Unique, a support group agency for families. View Image -
Figure 8.14.19 Interface for adding a LDDB phenotype term. View Image -
Figure 8.14.20 Pop‐up window showing selectable items to be printed. View Image
Videos
Literature Cited
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