DECIPHER: database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation

Abstract

The DECIPHER database (https://decipher.sanger.ac.uk/) is an accessible online repository of genetic variation with associated phenotypes that facilitates the identification and interpretation of pathogenic genetic variation in patients with rare disorders. Contributing to DECIPHER is an international consortium of >200 academic clinical centres of genetic medicine and ≥1600 clinical geneticists and diagnostic laboratory scientists. Information integrated from a variety of bioinformatics resources, coupled with visualization tools, provides a comprehensive set of tools to identify other patients with similar genotype-phenotype characteristics and highlights potentially pathogenic genes. In a significant development, we have extended DECIPHER from a database of just copy-number variants to allow upload, annotation and analysis of sequence variants such as single nucleotide variants (SNVs) and InDels. Other notable developments in DECIPHER include a purpose-built, customizable and interactive genome browser to aid combined visualization and interpretation of sequence and copy-number variation against informative datasets of pathogenic and population variation. We have also introduced several new features to our deposition and analysis interface. This article provides an update to the DECIPHER database, an earlier instance of which has been described elsewhere [Swaminathan et al. (2012) DECIPHER: web-based, community resource for clinical interpretation of rare variants in developmental disorders. Hum. Mol. Genet., 21, R37-R44].

Figure 1.

Discovering clusters of patients with a 6q25.3 deletion involved with intellectual disability. Search in DECIPHER for 6q25.3 identified patient 250481 with a 9.5-Mb deletion in 6q25.3. (A) Interactive visualization of genes overlapping deletion in patient 250481 and other patients that have similar deletions in 6q25.3 in DECIPHER and ISCA (17) databases. Overlapping genes are coloured by their propensity to display haploinsufficiency (18). (B) Prioritizing genes affected by a deletion event in patient 250481. List of all affected genes with associated properties. At least three genes have OMIM Morbid entries and are present in the curated list of genes known to be involved in developmental disorders (DDG2P). (C) Identifying other patients with shared phenotypes. Details of overlapping patients with shared phenotypes are highlighted in bold. Most patients appear to display intellectual disability and have a common overlap (see boxed area in Figure 1A) on ARID1B. (D) Gene ARID1B entry in the DDG2P database. Deletions affecting this gene are a cause of intellectual disability.

Figure 1.

Discovering clusters of patients with a 6q25.3 deletion involved with intellectual disability. Search in DECIPHER for 6q25.3 identified patient 250481 with a 9.5-Mb deletion in 6q25.3. (A) Interactive visualization of genes overlapping deletion in patient 250481 and other patients that have similar deletions in 6q25.3 in DECIPHER and ISCA (17) databases. Overlapping genes are coloured by their propensity to display haploinsufficiency (18). (B) Prioritizing genes affected by a deletion event in patient 250481. List of all affected genes with associated properties. At least three genes have OMIM Morbid entries and are present in the curated list of genes known to be involved in developmental disorders (DDG2P). (C) Identifying other patients with shared phenotypes. Details of overlapping patients with shared phenotypes are highlighted in bold. Most patients appear to display intellectual disability and have a common overlap (see boxed area in Figure 1A) on ARID1B. (D) Gene ARID1B entry in the DDG2P database. Deletions affecting this gene are a cause of intellectual disability.

Figure 2.

Combined sequence and CNV analysis (e.g. DECIPHER patient 273915). (A) Both CNV and sequence variants are shown in tabular form. The sequence variant summary information includes calculated consequences and transcript-based HGVS nomenclature. (B) Data from Ensembl VEP for all possible transcripts at given genomic position, with predicted consequences using SIFT (21) and PolyPhen (22). Transcript chosen by the depositor is shown in bold.

Figure 3.

Interactive display of variants in DECIPHER. (A) Genome browser showing both sequence and copy-number variation. Data from LSDB (26) and public HGMD (27) databases of sequence variation are also shown with DECIPHER syndrome entries that match these positions. (B) At higher zoom levels, the sequence variant is shown on the reference genome sequence. This view shows the G>A sequence variant with overlapping entries in DECIPHER syndromes and HGMD.