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.

Figure 1.

DECIPHER provides participating clinical genetics centres secure and private area for depositing patient phenotypic and genotypic information. Preliminary analysis and comparison of these data can be carried out against anonymized consented data to aid contact and collaboration with other clinicians with patients with similar variation. Once patient consent for data release has been obtained, these anonymized data are supplemented with information from various bioinformatics resources and shared with the larger DECIPHER community and within external genome browsers such as the Ensembl Genome Browser and the UCSC Browser.

Figure 2.

Search and analysis. (A) DECIPHER provides a simple search interface that supports many different types of queries (highlighted: search DECIPHER by chromosomal position 17p11.2). (B) List of overlapping DECIPHER patients with additional detail and annotated syndromes found matching query. (C) DECIPHER patient page showing variant detail (position, mean ratio, genes involved and inheritance), with external genome browser links (highlighted). Also shown is a graphical comparison of patient CNV overlaid on other DECIPHER patients having an overlapping variant. (D) DECIPHER Gene Data: description for every gene affected by the CNV, additional data including Online Mendelian Inheritance in man (OMIM), OMIM Morbid, and Haploinsufficiency Scores and external links to gene resources (highlighted). (E) DECIPHER Patient Overlap: other consented DECIPHER patients that have an overlapping CNV with the query patient, common phenotypes are shown in bold.

Figure 3.

Expert-reviewed syndrome resource in DECIPHER. (A) Karyotype view showing the location and nature of all DECIPHER syndromes. (B) DECIPHER expert overview for 17q21.31 deletion syndrome (11) with associated citations and external links to support groups and additional sources of information. (C) Detail for 22q11 deletion syndrome (65) showing genes involved in the syndrome with associated haploinsufficiency scores and external links to OMIM, OMIM Morbid and other data sources.