Introduction
The population prevalence of rare disease has recently been estimated to
be 3.5–5.9%, which equates to 263–446 million people affected
globally. A large proportion of these rare diseases, approximately 72%,
are known to have a genetic basis (Wakap et al ., 2020 PMID:
31527858). Advances in genomic technologies to determine causal
variants, such as whole‐exome sequencing, are identifying the genetic
basis of disease for only 25–40% of patients (Stranneheim et
al. , 2021, Quaio et al. , 2020, Sawyer et al. , 2016). As a
result, many patients undergoing diagnostic genetic testing do not
receive a genetic diagnosis, and often experience long delays which have
a substantial emotional impact on the family (Miller, 2021) and
significant healthcare costs (Monroe et al ., 2016). A genetic
diagnosis has multiple benefits for the patient and their family,
including better understanding of the prognosis, personalised treatment,
tailored management and surveillance, improved access to health and
social care, and increased reproductive choice (Wright et al .,
2018).
The number of rare Mendelian diseases with known molecular aetiology is
estimated to be 5,000–6,000 (Hartley et al ., 2018), however, for
the majority of disease-associated genes it is not known which variants
are disease-causing, and which are benign. Different pathogenic variants
in the same gene can cause different diseases, for example variants inFGFR3 can cause multiple diseases including Muenke Syndrome,
Hypochondroplasia, and Achondroplasia. Different diseases caused by
variants in the same gene must be considered distinct due to their
disparate clinical presentation and differing treatment options. The
sharing of patient level variants and phenotypes is therefore essential
to accelerate our understanding of the molecular basis of genetic
disease.
DECIPHER (Firth et al. , 2009; Swaminathan et al ., 2012;
Bragin et al ., 2014; Chatzimichali et al . 2015) is a
global web-based platform which shares phenotype-linked variant data
from rare disease patients (Fig. 1A). It is freely available via a web
interface athttps://www.deciphergenomics.org.
Approximately 40,000 of the patient records held by DECIPHER have
explicit patient consent for open sharing on the website (Fig. 1B).
These openly shared records contain more than 51,000 variants and more
than 172,000 phenotype terms. The integration of this phenotype and
variant data enables the discovery of new gene-disease and
variant-disease relationships, driving diagnosis and our understanding
of human biology. Since DECIPHER was established in 2004, the platform
has been used and cited in more than 2,600 published manuscripts.
Patient records in DECIPHER are deposited by academic clinical centres,
which are affiliated both to a hospital which oversees the treatment of
patients with genetic disorders, and to a local university department of
human/clinical genetics. Eligible centers
(https://www.deciphergenomics.org/join/overview)
can apply to join DECIPHER using an online application form. Data from a
centre is stored within a DECIPHER project, and a senior clinician at
that centre (clinical coordinator), sometimes in conjunction with a
senior clinical scientist (lab coordinator), has the responsibility for
approving/rejecting applications from individuals working at that centre
who wish to access the data in the project.
The platform supports the deposition of almost all types of genetic
variation, including sequence variants, short tandem repeats,
copy-number variants (CNVs) and large structural variants. Variant
interpretation interfaces are provided, including genome and protein
browsers, which contextualise genetic and phenotype information to
enable accurate interpretation. These interfaces integrate external
datasets such as the Genome Aggregation Database (gnomAD, Karczewskiet al ., 2020), which can be used to exclude variants seen at
appreciable frequency in the general population, in addition to disease
relevant datasets such as ClinVar (Landrum et al ., 2018 PMID:
29165669) and DECIPHER records themselves. DECIPHER also encourages the
use of global standards to promote good practice, including the American
College of Medical Genetics (ACMG) guidelines for sequence variant
interpretation (Richards et al., 2015) and ACMG/ClinGen technical
standards for interpreting CNVs (Riggs et al ., 2020).
In the following sections we present examples of the genotype/phenotype
data deposited and shared with the rare disease community. In addition
we present the tools provided by DECIPHER to assess the pathogenicity of
variants according to international standards, and the utility of
DECIPHER to map the clinically relevant parts of the genome.