DECIPHER

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A segment of the human reference genome, viewed using Ensembl with the DECIPHER track enabled. Red bars represent individual mutations for anonymous patients with deletions across this region, while green bars represent patients with duplications across this region. The region shown encompasses the segment of chromosome missing in patients with 17q21.3 recurrent microdeletion syndrome. DECIPHER example.png
A segment of the human reference genome, viewed using Ensembl with the DECIPHER track enabled. Red bars represent individual mutations for anonymous patients with deletions across this region, while green bars represent patients with duplications across this region. The region shown encompasses the segment of chromosome missing in patients with 17q21.3 recurrent microdeletion syndrome.

DECIPHER is a web-based resource and database of genomic variation data from analysis of patient DNA. [1] [2] [3] It documents submicroscopic chromosome abnormalities (microdeletions and duplications) and pathogenic sequence variants (single nucleotide variants - SNVs, Insertions, Deletions, InDels), from over 25000 patients and maps them to the human genome using Ensembl or UCSC Genome Browser. [1] [2] [4] In addition it catalogues the clinical characteristics from each patient and maintains a database of microdeletion/duplication syndromes, together with links to relevant scientific reports and support groups. [1] [5]

Contents

An acronym of DatabasE of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources, DECIPHER was initiated in 2004 at the Sanger Institute in the United Kingdom, funded by the Wellcome Trust. [1] However it is supported by an international research consortium, with patient data contributed by more than 240 clinical genetics centres from 33 countries. Each centre is represented by an experienced clinical geneticist and a senior molecular cytogeneticist. [6]

Aims

A schematic representation of a chromosome deletion. DECIPHER maps small deletions detected in patients to the reference genome produced by the Human Genome Project. Deletion of chromosome section.svg
A schematic representation of a chromosome deletion. DECIPHER maps small deletions detected in patients to the reference genome produced by the Human Genome Project.

DECIPHER was established in 2004 by Nigel Carter of the Wellcome Trust Sanger Institute and Helen Firth, a clinical genetics consultant at Addenbrooke's Hospital in Cambridge. It has three main aims: [6] [7]

As a tool for clinical geneticists, cytogeneticists and molecular biologists, DECIPHER is used to determine whether gene copy number variations identified in patients are of clinical significance. Members can visualise the genes within the region of DNA altered in their patients, and ascertain whether any are known to be implicated in disease. Chromosomal imbalances are a major cause of developmental delay, learning disabilities and congenital abnormalities and — according to Emily Niemitz writing in Nature Genetics — the database facilitates collaboration between researchers and clinicians who have patients with similar clinical characteristics, which can "assist in the discovery of new syndromes and in the recognition of genes of clinical importance." [4] [5]

Process

Patients are entered into DECIPHER by registered consortium members. Typically a clinical geneticist arranges for a chromosome analysis (usually microarray based) of a patient's DNA. A potential microdeletion/microduplication may be identified, but the medical significance is not known. [8] The clinician may enter the anonymised data into the restricted, password protected DECIPHER database and map the location and size of the chromosomal deletion/duplication to the reference genome. Using DECIPHER, the clinician can then identify the specific genes affected by the deletion/duplication, determine whether any have known clinical significance (for example, whether tumour suppressor genes have been deleted), [9] and view the region in the Ensembl genome browser to see whether there are any other consented patients in DECIPHER with overlapping deletion/duplications. [8] This enables a better ascertainment of whether a copy number change is a normal polymorphic variant, or the likely cause of the patient's clinical symptoms. The clinician can then counsel the patient on the likely significance of the deletion/duplication, and its implications for their health. [8]

Each patient's data is anonymized, and represented only by an ID with an associated genotype and set of clinical symptoms (phenotypes). Patient data is made accessible to other members of the consortium and viewable through Ensembl if a consent form is signed by the patient. [8] With informed consent, the anonymized deletion/duplication and phenotypes become available for view to DECIPHER consortium members and public users, with different levels of access (e.g. only logged users can see the contact details of the centre that entered the data). Public users who wish to find more information about a patient may send a request to DECIPHER, which then will forward it to the clinician coordinator responsible for the submitting center.

Most patients deposited in DECIPHER display genetic mutations with a very low occurrence in the general population. Hence the probability of the same clinicians encountering similar patients are also low. Since DECIPHER is opened to any accredited clinician or cytogeneticist from around the world, the chances of finding similar rare cases are significantly increased. This on-line sharing of clinical genetic information not only promotes better understanding of microdeletions/microduplications and their associated pathogenic phenotypes, it has also facilitated the discovery of new syndromes. [10] [11] [12] [13] As of January 2014, over 23000 patients have been entered into the DECIPHER database of which over 10000 are consented.

Ethics and privacy

The appropriate consent to enter patient data into DECIPHER is obtained by the submitting clinician. [14] Patient consent can be withdrawn at any time, and their data is removed. [7] Often children's records are displayed with the consent of their parents of guardians. DECIPHER advises that, when the child reaches the age of sixteen years, he or she be made aware of the entry and be given the opportunity to withdraw or continue as a participant. [7] Each member centre that uses DECIPHER obtains ethical approval from a research ethics committee in their own institution or country, where applicable. In the UK, the Information Commissioner's Office has been notified about DECIPHER in accordance with the Data Protection Act 1998. [14] The project is overseen by an advisory board representatives from the field of human genetics, computational biology, ethics and law. [15]

To ensure information privacy, data is served over an encrypted TLS/SSL connection. Only trusted individuals from recognized medical research centres can access the identity of the center that submitted another patient (permitting them to contact the patient's clinicians should they wish to collaborate). Members of the public may browse consented anonymized patient data in DECIPHER and Ensembl, without the identity of the submitting centre being shown. [8] [14]

See also

Related Research Articles

<span class="mw-page-title-main">Wellcome Sanger Institute</span> British genomics research institute

The Wellcome Sanger Institute, previously known as The Sanger Centre and Wellcome Trust Sanger Institute, is a non-profit British genomics and genetics research institute, primarily funded by the Wellcome Trust.

Smith–Magenis syndrome (SMS), also known as 17p-microdeletion syndrome, is a microdeletion syndrome characterized by an abnormality in the short (p) arm of chromosome 17. It has features including intellectual disability, facial abnormalities, difficulty sleeping, and numerous behavioral problems such as self-harm. Smith–Magenis syndrome affects an estimated between 1 in 15,000 to 1 in 25,000 individuals.

<span class="mw-page-title-main">Medical genetics</span> Medicine focused on hereditary disorders

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<span class="mw-page-title-main">22q13 deletion syndrome</span> Rare genetic syndrome

22q13 deletion syndrome, known as Phelan–McDermid syndrome (PMS), is a genetic disorder caused by deletions or rearrangements on the q terminal end of chromosome 22. Any abnormal genetic variation in the q13 region that presents with significant manifestations (phenotype) typical of a terminal deletion may be diagnosed as 22q13 deletion syndrome. There is disagreement among researchers as to the exact definition of 22q13 deletion syndrome. The Developmental Synaptopathies Consortium defines PMS as being caused by SHANK3 mutations, a definition that appears to exclude terminal deletions. The requirement to include SHANK3 in the definition is supported by many but not by those who first described 22q13 deletion syndrome.

<span class="mw-page-title-main">2p15-16.1 microdeletion syndrome</span> Medical condition

2p15-16.1 microdeletion is an extremely rare genetic disorder caused by a small deletion in the short arm of human chromosome 2. First described in two patients in 2007, by 2013 only 21 people have been reported as having the disorder in the medical literature.

<span class="mw-page-title-main">Koolen–De Vries syndrome</span> Rare genetic disorder caused by a deletion of six genes

Koolen–De Vries syndrome (KdVS), also known as 17q21.31 microdeletion syndrome, is a rare genetic disorder caused by a deletion of a segment of chromosome 17 which contains six genes. This deletion syndrome was discovered independently in 2006 by three different research groups.

<span class="mw-page-title-main">8p23.1 duplication syndrome</span> Medical condition

8p23.1 duplication syndrome is a rare genetic disorder caused by a duplication of a region from human chromosome 8. This duplication syndrome has an estimated prevalence of 1 in 64,000 births and is the reciprocal of the 8p23.1 deletion syndrome. The 8p23.1 duplication is associated with a variable phenotype including one or more of speech delay, developmental delay, mild dysmorphism, with prominent forehead and arched eyebrows, and congenital heart disease (CHD).

<span class="mw-page-title-main">3q29 microdeletion syndrome</span> Medical condition

3q29 microdeletion syndrome is a rare genetic disorder resulting from the deletion of a segment of chromosome 3. This syndrome was first described in 2005.

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1q21.1 deletion syndrome is a rare aberration of chromosome 1. A human cell has one pair of identical chromosomes on chromosome 1. With the 1q21.1 deletion syndrome, one chromosome of the pair is not complete, because a part of the sequence of the chromosome is missing. One chromosome has the normal length and the other is too short.

<span class="mw-page-title-main">1q21.1 duplication syndrome</span> Medical condition

1q21.1 duplication syndrome, also known as 1q21.1 microduplication, is an uncommon copy number variant associated with several congenital abnormalities, including developmental delay, dysmorphic traits, autism spectrum disorder, and congenital cardiac defects. Common facial features include frontal bossing, hypertelorism, and macrocephaly. Around 18 and 29% of patients with 1q21.1 microduplications have congenital cardiac abnormalities. 1q21.1 duplication syndrome is caused by microduplications of the BP3-BP4 region. 18-50% are de novo deletions and 50-82% inherited from parents. The 1q21.1 area, one of the largest regions in the human genome, is highly susceptible to copy number variation due to its frequent low-copy duplications. Whole exon sequencing and quantitative polymerase chain reaction can provide a precise molecular diagnosis for children with 1q21.1 microduplication syndrome.

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<span class="mw-page-title-main">GRXCR1</span> Protein-coding gene in the species Homo sapiens

Glutaredoxin domain-containing cysteine-rich protein 1 is a protein that in humans is encoded by the GRXCR1 gene.

<span class="mw-page-title-main">Microdeletion syndrome</span> Syndrome caused by chromosomal deletion

A microdeletion syndrome is a syndrome caused by a chromosomal deletion smaller than 5 million base pairs spanning several genes that is too small to be detected by conventional cytogenetic methods or high resolution karyotyping. Detection is done by fluorescence in situ hybridization (FISH). Larger chromosomal deletion syndromes are detectable using karyotyping techniques.

<span class="mw-page-title-main">Genotype-first approach</span>

The genotype-first approach is a type of strategy used in genetic epidemiological studies to associate specific genotypes to apparent clinical phenotypes of a complex disease or trait. As opposed to “phenotype-first”, the traditional strategy that has been guiding genome-wide association studies (GWAS) so far, this approach characterizes individuals first by a statistically common genotype based on molecular tests prior to clinical phenotypic classification. This method of grouping leads to patient evaluations based on a shared genetic etiology for the observed phenotypes, regardless of their suspected diagnosis. Thus, this approach can prevent initial phenotypic bias and allow for identification of genes that pose a significant contribution to the disease etiology.

<span class="mw-page-title-main">MIPEP</span> Protein-coding gene in the species Homo sapiens

Mitochondrial intermediate peptidase is an enzyme that in humans is encoded by the MIPEP gene. This protein is a critical component of human mitochondrial protein import machinery involved in the maturing process of nuclear coded mitochondrial proteins that with a mitochondrial translocation peptide, especially those OXPHOS-related proteins.

<span class="mw-page-title-main">Structural variation in the human genome</span> Genomic alterations, varying between individuals

Structural variation in the human genome is operationally defined as genomic alterations, varying between individuals, that involve DNA segments larger than 1 kilo base (kb), and could be either microscopic or submicroscopic. This definition distinguishes them from smaller variants that are less than 1 kb in size such as short deletions, insertions, and single nucleotide variants.

<span class="mw-page-title-main">Xp11.2 duplication</span> Genetic disorder

Xp11.2 duplication is a genomic variation marked by the duplication of an X chromosome region on the short arm p at position 11.2, defined by standard karyotyping (G-banding). This gene-rich, rearrangement prone region can be further divided into three loci - Xp11.21, Xp11.22 and Xp11.23. The duplication could involve any combination of these three loci. While the length of the duplication can vary from 0.5Mb to 55 Mb, most duplications measure about 4.5Mb and typically occur in the region of 11.22-11.23. Most affected females show preferential activation of the duplicated X chromosome. Features of affected individuals vary significantly, even among members of the same family. The Xp11.2 duplication can be 'silent' - presenting no obvious symptoms in carriers - which is known from the asymptomatic parents of affected children carrying the duplication. The common symptoms include intellectual disabilities, speech delay and learning difficulties, while in rare cases, children have seizures and a recognizable brain wave pattern when assessed by EEG (electroencephalography).

<span class="mw-page-title-main">17q12 microdeletion syndrome</span> Rare genetic anomaly in humans

17q12 microdeletion syndrome, also known as 17q12 deletion syndrome, is a rare chromosomal anomaly caused by the deletion of a small amount of material from a region in the long arm of chromosome 17. It is typified by deletion of the HNF1B gene, resulting in kidney abnormalities and renal cysts and diabetes syndrome. It also has neurocognitive effects, and has been implicated as a genetic factor for autism and schizophrenia.

<span class="mw-page-title-main">DiGeorge syndrome</span> Medical condition caused by chromosomal abnormality

DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent infections, developmental disability, intellectual disability and cleft palate. Associated conditions include kidney problems, schizophrenia, hearing loss and autoimmune disorders such as rheumatoid arthritis or Graves' disease.

References

  1. 1 2 3 4 Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, et al. (April 2009). "DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources". Am. J. Hum. Genet. 84 (4): 524–33. doi:10.1016/j.ajhg.2009.03.010. PMC   2667985 . PMID   19344873.
  2. 1 2 Swaminathan GJ; Bragin E; Chatzimichali EA; Corpas M; et al. (2012). "DECIPHER: web-based community resource for clinical interpretation of rare variants in developmental disorders". Hum. Mol. Genet. 21 (R1): R37–R44. doi:10.1093/hmg/dds362. PMC   3459644 . PMID   22962312.
  3. ↑ Bragin E; Chatzimichali EA"; et al. (2014). "DECIPHER: database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation". Nucleic Acids Res. 42 (Database issue): D993–D1000. doi:10.1093/nar/gkt937. PMC   3965078 . PMID   24150940.
  4. 1 2 Stewart, A; Brice, P; Burton, H (2007). Genetics, health care, and public policy: an introduction to public health genetics . Cambridge University Press. p.  159. ISBN   978-0-521-52907-5.
  5. 1 2 Niemitz, E (2009). "DECIPHERing chromosomal imbalances". Nature Genetics. 41 (5): 514. doi: 10.1038/ng0509-514 .
  6. 1 2 "About DECIPHER". Wellcome Trust Sanger Institute. Retrieved 12 February 2014.
  7. 1 2 3 Firth, HV (January 2009). "Welcome to the DECIPHER database: An introduction for Families" (PDF). Wellcome Trust Sanger Institute. Retrieved 12 February 2014.[ permanent dead link ]
  8. 1 2 3 4 5 Firth, HV. "Data Flow Chart for the DECIPHER Database" (PDF). Wellcome Trust Sanger Institute. Archived from the original (PDF) on 19 May 2015. Retrieved 12 February 2014.
  9. ↑ Genes of established clinical significance, including those listed in OMIM, are highlighted as are imprinted genes.
  10. ↑ Shaw-Smith C, Redon R, Rickman L, et al. (April 2004). "Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features". J. Med. Genet. 41 (4): 241–8. doi:10.1136/jmg.2003.017731. PMC   1735726 . PMID   15060094.
  11. ↑ Shaw-Smith C, Pittman AM, Willatt L, et al. (September 2006). "Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability". Nat. Genet. 38 (9): 1032–7. doi:10.1038/ng1858. PMID   16906163. S2CID   38047848.
  12. ↑ Zahir F, Firth HV, Baross A, et al. (September 2007). "Novel deletions of 14q11.2 associated with developmental delay, cognitive impairment and similar minor anomalies in three children". J. Med. Genet. 44 (9): 556–61. doi:10.1136/jmg.2007.050823. PMC   2597953 . PMID   17545556.
  13. ↑ Malan V, Raoul O, Firth HV, et al. (September 2009). "19q13.11 deletion syndrome: a novel clinically recognisable genetic condition identified by array comparative genomic hybridisation". J. Med. Genet. 46 (9): 635–40. doi:10.1136/jmg.2008.062034. PMID   19126570. S2CID   8491797.
  14. 1 2 3 Firth, HV. "Ethical framework for DECIPHER" (PDF). Wellcome Trust Sanger Institute. Retrieved 24 June 2010.[ permanent dead link ]
  15. ↑ "DECIPHER Advisory Board". Wellcome Trust Sanger Institute. Retrieved 24 June 2010.

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