CHD:FAQ

[edit] Genes and phenotypes

[edit] CHD type

[edit] Which genes are known for causing a specific CHD type?

Select the CHD type of interest in the AEPC list or directly by using the search box at the top of the page. Syndromic and non-syndromic genes and studies supporting this gene-phenotype association, are enlisted on the page of the CHD type of interest. Other information concerning this CHD type:

• pie diagram showing gene mutations in non-syndromic genes causing the CHD type (at the top of the page).
• chromosomal imbalances (deletions, duplications and translocation breakpoints) and linkage regions associated with this CHD type are overviewed at the bottom of the page or can be displayed by clicking on the chromosomal map above the pie diagram.

[edit] How is the level of support of a gene-phenotype association defined?

The level of support of a gene-phenotype association is defined upon the incidence of the association and the number of independent publications, confirming this association. The level of support of the genotype-phenotype association is indicated by a colour:

• unconfirmed: a single case report
• no good correlation between CHD type and candidate gene
• likely: 2 or more patients (with CHD and a mutation in the candidate gene)
• confirmed: 2 or more independent reports > 1% incidence

Moreover, the support for every single gene mutation was defined by 3 domains:

1. Genetic evidence:
   1. Inheritance of the mutation:
      • A de novo mutation
      • Segregation in the family (autosomal dominant, autosomal recessive, X-linked)
   2. Incidence of the mutation in the population:
      • Number of patients with the mutation in the investigated population
      • Number of independent reports
      • Number of normal controls carrying the mutation
2. Functional studies: e.g. animal models
3. In silico prediction: e.g. Polyphen (functional domain, Evolutionary conserved region,...)

[edit] Genes

[edit] Which phenotypes are assiociated with a specific gene?

Select the gene of interest in the list of genes currently associated with CHDs or directly by using the search box at the top of the page. Syndromic and non-syndromic phenotypes and studies supporting this gene-phenotype association, are enlisted on the page of the gene of interest. Other information concerning this gene:

• pie diagram showing the relative incidence of the CHD types associated with this gene (at the top of the page).
• overview of chromosomal imbalances and translocation breakpoints comprising the gene of interest
• diagram of protein interactions partners of the gene of interest
• table overviewing the gene mutations associated with a CHD type, supported by genetic evidence, in silico prediction and functional studies.

[edit] How to add a new gene-phenotype association?

• Select the gene of interest in the list of genes currently associated with CHDs or directly by using the search box at the top of the page. You will be redirected to a new gene page if the gene is not currently known to be associated with CHDs.
• Click on 'add another phenotype' (syndromic or non-syndromic)
• Fill in the 'gene-phenotype association' query:
  • support (defining the level of support: see above)
  • phenotype
  • reference (PMID)
  • inheritence and/or associated features (if syndromic)
  • incidence (number of patients tested and number of mutations found)
• Save and go back to the gene page
• Add the study supporting this new gene-phenotype association (instructions for adding a new study: see below)

[edit] How to add a new study supporting a gene-phenotype association?

• If this gene-phenotype association does not exist yet, please first create this association following the instructions above.
• Click on 'add another study' beneath the corresponding gene-phenotype association
• Fill in the 'mutation analysis' query:
  • study type (case/family report or population study)
  • numbers of subjects with this CHD type tested
  • numbers of subjects with this CHD type carrying a mutation
  • reference (PMID)
  • comments: briefly summarize the study
• Save and go back to the gene page: your data will be added to the pie diagram at the top of the page

[edit] How to add a gene mutation?

• After adding and saving a new study you are able to add gene mutation information by clicking the edit sign next to the PMID of the study.
• Click on 'add mutation details' beneath the 'mutation analysis' query
• Fill in the 'mutation details' query:
  • mutation (nucleotide and protein) (see nomenclature)
  • genetic evidence (dominance, familial/sporadic, segregation)
  • mutation incidence in this study
  • functional studies ('in vitro' studies, animal studies,...)
  • in silico prediction (computational model predicting the effect of the mutation on protein structure and function)
  • comments

[edit] Chromosomal regions

[edit] CHD type

[edit] Which chromosomal imbalances are associated with a specific CHD type?

• Either select the CHD type of interest in the AEPC list or directly by using the search box at the top of the page. Chromosomal imbalances (deletions, duplications and translocation breakpoints) and linkage regions associated with this CHD type are overviewed at the bottom of the page or can be displayed by clicking on the chromosomal map above the pie diagram at the top of the page.
• Either go directly to the map and select the CHD type of interest in the display options box. A selection of the chromosome(s), type of imbalance or source can be made in this box as well.

[edit] Regions

[edit] Which chromosomal aberrations, linkage regions and/or translocation breakpoints are known to be associated with CHD?

Chromosomal aberrations, linkage regions and translocation breakpoints are shown on the chromosomal map and are displayed as a coloured bar at the right side of the chromosome of interest. By scrolling over a bar, the cardiac phenotype associated with the chromosomal defect, can be seen. More data concerning the size of the imbalance or associated clinical details can be obtained, by a double click on the bar (see below: which clinical features are associated with a chromosomal aberration or linkage region?).

• deletion
• duplication
• linkage region
• translocation breakpoint

[edit] Does a chromosomal region comprise known CHD genes?

Check the region of interest on the map. Genes known for causing CHDs when mutated, can be displayed on the chromosomal map (orange bar on the left side of the chromosome of interest) by selecting this track in the display options box. Double click on this gene to acces the gene page. The region of interest can also be seen in the Ensemble genome browser([1]), by double click on the corresponding band of the chromosome (e.g. 8p23.1). Known cardiac genes and cardiac syndromes are displayed in the Ensemble genome browser as a CHDWiki DAS track. Chromosomal regions (deletions, duplications, linkage regions and translocation breakpoints) associated with CHD are displayed as a CHDBench DAS track (How to display CHDWiki features in the Ensembl genome browser: see below). If no known CHD genes are present in the region, candidate genes for the heart defect can be prioritized (instructions for gene prioritization: see below).

[edit] Which clinical features are associated with a chromosomal aberration, translocation breakpoint or linkage region?

• chromosomal imbalance: click on the coloured bar corresponding with a
  deletion
  or a
  duplication
  (at the right side of the chromosome of interest) to view the cytogenetic report of the subject in CHDBench. Notice: CHDBench only contains chromosomal imbalances detected by means of array Comparative Genomic Hybridisation (aCGH).
  • molecular data: can be viewed by selecting chromosomal defect (size of the aberration, flanking clones, method of confirmation and link to Ensemble genome browser) or can be appreciated on a graphical view by selecting karyogram
  • clinical data: can be viewed either as free text, either as an list of key words, both cardiac (AEPC codes) and non-cardiac (LDDB terms) (see below: how to add a new case report?)
  • to have an overview of all CHDWiki case reports, select the link my reports (or karyogram for a graphical overview) at the top of the page
• linkage region: click on the coloured bar corresponding a
  linkage region
  (at the right side of the chromosome of interest) to view the size of the region and the associated clinical details in a table at the bottom of the CHD page (linkage regions are not present in CHDBench).
• translocation breakpoint: click on the coloured bar corresponding a
  translocation breakpoint
  (at the right side of the chromosome of interest) to view the size of the region and the associated clinical details in a table at the bottom of the CHD page (translocation breakpoints are not present in CHDBench).

[edit] How to add a new case report?

• add patients with a translocation on this page or at the bottom of the corresponding CHD page (select add another translocation):
  • phenotype: CHD type
  • region: use either the bands containing the translocation breakpoints (e.g. 1 q42), either the base pairs (e.g. 1 234119956 234219956)
  • reference: PMID
  • comment: please add the karyogram (giving an overview of all the breakpoint containing regions) of the patient; any additional clinical features can be provided here as well.
• add linkage between a genome region and a CHD on this page or at the bottom of the corresponding CHD page (select add another region):
  • phenotype: CHD type
  • region: use either the bands containing the translocation breakpoints (e.g. 1 q42), either the base pairs (e.g. 1 234119956 234219956), either the markers (e.g. D5S2088 (must start with D)).
  • reference: PMID
  • comment: any additional clinical features can be provided here.

[edit] How to prioritize genes in a chromosomal region?

Using this Wiki, it is possible to rank candidate genes according to their putative function in cardiogenesis. This is done by a software built to perform an in silico prioritisation ("Endeavour"). For detail on the functioning and validation of this software we refer to the manuscript by Aerts et al that describes it's algorithm. Endeavour has also been built into this Wiki on the Prioritize page, where further instructions can be found on how to use it.

[edit] Other questions

[edit] How to edit a text in the CHDWiki?

For the use of text editors with the CHDWiki, see Wiki Syntax [2].

[edit] How can I see CHDWiki features in the Ensembl genome browser?

Follow the steps detailed here.