Databases and Web-tools

Question 1

Why are online databases, resources and tools becoming increasingly important in clinical diagnostics?

Answer 1

• A massive increase in the amount of DNA sequence information being generated gloabelly has been driven by the advent of massively parallel sequencing.
• Huge amounts of data make manual manipulation alone impractical therefore the use of in silico tools has enabled more efficient analysis of data.
• Very rare disorders require the ability for separate groups to share data to aid interpretation of such rare cases
• Databases of variants in unaffected people are also needed to interpret genome wide data

Question 2

When using databases, clinical laboratories should consider what factors?

Answer 2

• Determine how frequently the database is updated, whether data curation is supported, and what methods were used for curation
• Confirm the use of HGVS nomenclature and determine the genome build and transcript references used for naming variants
• Determine the degree to which data are validated for analytical accuracy (e.g., low-pass next generation sequencing versus Sanger-validated variants) and evaluate any quality metrics that are provided to assess data accuracy, which may require reading associated publications
• Determine the source and independence of the observations listed

Question 3

What are the General Limitations of using external databases?

Answer 3

1. Accuracy of the data
2. Patient consent and confidentiality associated with public sharing of clinical data
3. Intellectual property rights of information
4. duplicate entries being counted as independant entries
5. Frequency of update/curation
6. Clinical status of participant ?affected/unaffected
7. Free or license required?

Question 4

List commonly used tools for browsing reference genome sequences.

Answer 4

• Ensembl Genome Browser
• UCSC Genome Bioinformatics
• NCBI Genome
• Locus Reference Genome (LRG)
  
  • Joint venture between the NCBI and EBI
  • Records contain internationally recognized stable reference sequences designed specifically for reporting clinically relevant sequence variants.

Question 5

List commonly used databases of population variant data.

Answer 5

• Exome Aggregation Consortium (ExAC): 60,706 unrelated individuals
• NHLBI Exome Variant Server (EVS):

Created to discover genes contributing to heart, lung and blood disorders. 6503 samples taken from cardiovascular and respiratory disease cohorts (can be used to rule out severe congenital variants).

• 1000 Genomes Project
• genome Aggregation Database (gnomAD): intergrates ExAC, EVS, 1kg. 123,136 WES, 15,496 WGS from unrelated individuals
• dbSNP - SNVs: direct submissions - full of rubbish
• dbVAR - CNVs
• Database of Genomic Variants (DGV) - CNVs - non-direct submission - good quality

Question 6

What is a Locus specific mutation database (LSDBs)?

Answer 6

• Repositories that contain variation information for genes and proteins that have disease relevance
• Usually the primary and most trusted variation information source as they are curated and maintained by experts in the gene and disease
• Lists of LSDBs available
  
  • HGVS: http://www.hgvs.org/locus-specific-mutation-databases
  • LOVD: http://grenada.lumc.nl/LSDB_list/lsdbs

Question 7

What were the recommendations for LSDBs and Classification of Variants proposed by Greenblatt et al, 2008?

Answer 7

• LSDBs should only report a conclusion related to pathogenicity if a consensus has been reached by an expert panel representing different areas of expertise (clinical, diagnostic, molecular, and computational).
• The system used to classify variants should be standardised.
• Evidence supporting a conclusion of pathogenic or neutral should be reported in the database, including the source and the criteria used for assignment.
• Variants should only be classified as pathogenic or not if more than one type of evidence has been considered.
• All instances of all variants should be recorded.

Question 8

What is the Human Variome Project (HVP)?

Answer 8

• Was initiated in 2006 to foster discussion around how disparate work of genetic variation database curators could be connected globally.
• Aimed to standardise nomenclature and data presentation
• Developed Country Nodes to document variation within a specific population.
• The HVP, HGVS and the GEN2PHEN project are all working toward standardized variation and pathogenicity data presentation.

Question 9

What are the most commonly used public databased for Rare Diseases?

Answer 9

• DECIPHER: DatabasE of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources
• ClinVar (SNVs/CNVs)
• Human Gene Mutation Database (HGMD)
• OMIM (Online Mendelian Inheritance in Man)
• ECARUCA (European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations)

Question 10

What are the most commonly used public databased for Oncology?

Answer 10

• Catalogue of Somatic Mutations in Cancer (COSMIC)
• Mitelman Database of Chromosome Aberrations and Gene Fusions in cancer
• Atlas of Genetics and Cytogenetics in Oncology and Haematology