DECIPHER: web-based, community resource for clinical interpretation of rare variants in developmental disorders

Abstract

Patients with developmental disorders often harbour sub-microscopic deletions or duplications that lead to a disruption of normal gene expression or perturbation in the copy number of dosage-sensitive genes. Clinical interpretation for such patients in isolation is hindered by the rarity and novelty of such disorders. The DECIPHER project (https://decipher.sanger.ac.uk) was established in 2004 as an accessible online repository of genomic and associated phenotypic data with the primary goal of aiding the clinical interpretation of rare copy-number variants (CNVs). DECIPHER integrates information from a variety of bioinformatics resources and uses visualization tools to identify potential disease genes within a CNV. A two-tier access system permits clinicians and clinical scientists to maintain confidential linked anonymous records of phenotypes and CNVs for their patients that, with informed consent, can subsequently be shared with the wider clinical genetics and research communities. Advances in next-generation sequencing technologies are making it practical and affordable to sequence the whole exome/genome of patients who display features suggestive of a genetic disorder. This approach enables the identification of smaller intragenic mutations including single-nucleotide variants that are not accessible even with high-resolution genomic array analysis. This article briefly summarizes the current status and achievements of the DECIPHER project and looks ahead to the opportunities and challenges of jointly analysing structural and sequence variation in the human genome.

Genetic, environmental, and epigenetic factors involved in CAKUT

“…Furthermore, mutations in TRAP1 have been detected at a frequency of 0.15% in CAKUT and 0.6% in CAKUT with VACTERL (vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula and/or esophageal atresia, renal and radial anomalies and limb defects). 41,42 Recessive mutations in both genes are, therefore, a novel but rare cause of these conditions.…”

“…Databases, such as PhenomeCentral, 41 DECIPHER, 42 ClinGen, 43 LOVD, 44 and Matchmaker Exchange 45 are being assembled to enable the discovery of patients with similar phenotypes who have had their genome sequenced at different centres but who share the same candidate variants. The advantage of co-segregation analysis was illustrated when genome-wide linkage analysis was used in a family with seven affected members together with whole exome sequencing in two of the family members, in order to identify a new candidate gene for CAKUT.…”

“…Public databases, such as ECARUCA, 63 DECIPHER, 42 ISCA, 64 PubMed, and the Database of Genomic Variants, 65 are available to check whether newly identified CNVs already exist in healthy or diseased individuals. A systematic analysis of CNVs recorded in the DECIPHER database showed that CNV-associated phenotypes overlap more frequently than expected by chance with those of Mendelian diseases caused by single genes that are located within or adjacent to the reported CNVs.…”

A Novel Partial Duplication of ZEB2 and Review of ZEB2 Involvement in Mowat-Wilson Syndrome

“…Seven other individuals with copy number gains involving part or all of ZEB2 were identified within the DECIPHER (https://decipher.sanger.ac.uk) [Firth et al, 2009;Swaminathan et al, 2012] and ISCA (International Standards for Cytogenomic Arrays) clinical genomic resource databases (http://dbsearch.clinicalgenome.org). Direct comparisons between these previous reports and the current patient may be difficult as most of the previous duplications are much larger and contained additional genes.…”

The impact of integrated omics technologies for patients with rare diseases

“…This in turn has resulted in > 250 publications citing use of EuroBioBank materials [48]. In the genetics field, DECIPHER (DatabasE of Genomic variants and Phenotype in Humans Using Ensembl Resources) is an interactive web-based database which incorporates a range of bioinformatic tools designed to aid the interpretation of genomic variants [49]. To date > 200 centres have contributed data to this database, which equates to > 10,000 cases in total.…”