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## Genome Variation - Chromosomal Aberrations & Others
​
### Examples with proposed descriptors
<table>
<tr>
<th>Condition</th>
<th>Descriptor</th>
<th>Type</th>
<th>Comments </th>
</tr>
<tr>
<td>Klinefelter Syndrome (47,XXY)</td>
<td>GRCh38 (chrX:add)</td>
<td>
<span dir="">Aneuploidy</span>
</td>
<td>
</td>
</tr>
<tr>
<td>
[Turner Syndrome](https://www.merckmanuals.com/professional/pediatrics/chromosome-and-gene-anomalies/turner-syndrome)
</td>
<td>GRCh38 (chrX:del)</td>
<td>
<span dir="">Aneuploidy</span>
</td>
<td>
</td>
</tr>
<tr>
<td>47,XYY Syndrome</td>
<td>GRCh38 (chrY:add)</td>
<td>
<span dir="">Aneuploidy</span>
</td>
<td>
</td>
</tr>
<tr>
<td>
[Trisomy 18](https://www.merckmanuals.com/professional/pediatrics/chromosome-and-gene-anomalies/trisomy-18)
</td>
<td>GRCh38 (chr18:add)</td>
<td>
<span dir="">Aneuploidy</span>
</td>
<td>
</td>
</tr>
<tr>
<td>Down Syndrome (Trisomy 21)</td>
<td>GRCh38 (chr21:add)</td>
<td>
<span dir="">Aneuploidy</span>
</td>
<td>
</td>
</tr>
<tr>
<td>
<div>
<div>Down Syndrome (Robertsonian translocation)</div>
</div></td>
<td>
<span dir="">GRCh38 (chr21q10;chr14q10) - \[Down syndrome, unbalanced thus partial trisomy 21\]<br>GRCh38 (chr21q;chr14q10),(chr21:del),(chr14:del) - \[Variant for balanced carrier\]</span>
</td>
<td>
<span dir="">Aneuploidy</span>
</td>
<td>
</td>
</tr>
<tr>
<td>Fragile X syndrome</td>
<td>
<span dir="">GRCh38 (chrX:147912050-147912052)x201 - \[ClinVar sentinal for "200+" repeats variant, likely pathogenic\]<br>GRCh38 (chrX:147912050-147912052)x201,500 - \[generalized CNV for "all" likely pathogenic variants resulting in fragile X\]</span>
</td>
<td>Poly Nucleotide Repeat</td>
<td>
</td>
</tr>
<tr>
<td>
<div>
<div>Isochromosome (e.g. leading to Turner syndrome)</div>
</div></td>
<td>
<span dir="">GRCh38 (chrXq10;chrXq10),(chrXp:del) - \[form of Turner syndrome, p-arm loss of chrX\]</span>
</td>
<td>Other - Isochromosome</td>
<td>
</td>
</tr>
<tr>
<td>
<div>
<div>Ring chromosome (many associated conditions)</div>
</div></td>
<td>
<span dir="">GRCh38 (chr14p;chr14q) - \[associated with epilepsy and mental retardation\]</span>
</td>
<td>Other - Ring chromosome</td>
<td>
</td>
</tr>
<tr>
<td>Velocardiofacial syndrome</td>
<td>\[The specific microdeletion(s) genomic variants should be provided as SV. Vague "some microdeletions somewhere in a band of the q-arm" not supported. Deletion of whole 22q11.2 cytoband supported via equivalent genomic coordinates; best as a deletion SV than an x0 CNV\]</td>
<td>Structural Variant</td>
<td>
</td>
</tr>
</table>
### Context of this Interim/Proposed Descriptors
​
* Aim is to have descriptors that cover additional human genome variants, in this case large chromosomal abverrations, to support imminent new curation activities by the ACI group.
* By having proposed descriptors that clearly/uniqueky cover such variants, the ACI members can fill in the agreed upon descriptor syntax now, even in advance of CAR extension support for these.
* Furthermore, as "proposed" descriptors the descriptors documented below _may change to a very different form_ when fully implemented in the registry. In particular, ones that are weakly coordinate based may become overtly coordinate based for registration.
......@@ -9,10 +155,12 @@
- It is also possible that the registry may accept these interim syntaxes and itself convert to its preferred form.
* !!! NOTE: !!! To emphasize that last point, these descriptors should not be considered syntax that the registry will exactly support.
- These do not set a precedent or specification for the registry.
- But they do provide guidance and descriptors to consider.
​
- But they do provide guidance and descriptors to consider. ​
### Approach
​
* SV-like descriptors
* Assembly doesn't really matter for these
* Employ composition
......@@ -23,20 +171,22 @@
- `q10` is 0-length centromere (this is a genotyping standard) from q side and can be used for arm-fusions
- Not a stainable cytoband obviously.
- Similarly `p10` is 0-length centromere from the p size and can be used for arm-fusions
- For descriptors employing bands (these are large scale chromosomal abberrations after all) _other than the `p10/q10` special case_, we may translate them to genomic coordinates based on band definitions.
. Or we may decide the arm-based definitions are the "preferred" variant syntax for this scale. Must decide.
- For descriptors employing bands (these are large scale chromosomal abberrations after all) _other than the `p10/q10` special case_, we may translate them to genomic coordinates based on band definitions. . Or we may decide the arm-based definitions are the "preferred" variant syntax for this scale. Must decide.
* Currently, described as variation to the haploid set.
- This raises questions for aneuploidies of sex chromosomes, since it is not "context free" and any sydromes will depend on set of _non-variant_ chromosomes (additional X is a great example of "not context free" variation)
### Aneuploidy
Easy
​
Easy ​
#### Missing chr
* Adapted from SV descriptor syntax:
- `GRCh38 (chr8:del)`
- `GRCh38 (chrX:del)` - Turner Syndrome (one kind)
​
- `GRCh38 (chrX:del)` - Turner Syndrome (one kind) ​
#### Additional chr
* Adapted from SV descriptor syntax for `dup` (don't like it):
- `GRCh38 (chr8)x2`
- `GRCh38 (chrY)x2`
......@@ -49,61 +199,72 @@ Easy
- However, the condition will be dependent on patient's diploid set.
- i.e. clinical actionability and even phenotype will depend on more than just presence of a genomic variant.
- Currently, such context considerations is not the realm of variant registry, rather it is exactly the kind of consideration the ACI effort would be concerned about: additional context of the patient (age, but also sex), syndrome risks, and various Outcome-Interventions.
- Thus, so far, we are convoluting variant descriptors with patient context.
​
- Thus, so far, we are convoluting variant descriptors with patient context. ​
#### Combine multiple, including with other SV:
​
* `GRCh38 (chr8:del),(chrY:add)`
* `GRCh38 (chrX:del),(chr1:2811131-2812146inv),(chr1:2811953-2812146)x2`
​
* `GRCh38 (chrX:del),(chr1:2811131-2812146inv),(chr1:2811953-2812146)x2` ​
### Robertsonian translocation
W.L.O.G.
​
From descriptor of a human genomic variant, must consider the balanced healthy (as far as we know now) carrier from the variation that can lead to another kind of Down Syndrome
​
W.L.O.G. ​ From descriptor of a human genomic variant, must consider the balanced healthy (as far as we know now) carrier from the variation that can lead to another kind of Down Syndrome ​
* `GRCh38 (chr21q;chr14q10),(chr21:del),(chr14:del)` - Look, it's simple: fusion of long arms of 21 and 14 at their centromeres, combined with loss of normal chr21 and normal chr14 in the haploid set to complete the Robertsonian translocation for a _balanced_ carrier.
* `GRCh38 (chr21q;chr14q10),(chr21p10;chr14p10),(chr21:del),(chr14:del)` - Here the balanced carrier has ALSO retained the fusion fragment of the two p arms [rare, mainly for illustration here]
* `GRCh38 (chr21q;chr14q10),(chr21p10;chr14p10),(chr21:del),(chr14:del)` - Here the balanced carrier has ALSO retained the fusion fragment of the two p arms \[rare, mainly for illustration here\]
* `GRCh38 (chr21q10;chr14q10)` - But the `:del` are missing, meaning the haploid set has both chr21 and chr14 as well!
- UNbalanced case.
- Down Syndrom due to effective [partial] trisomy 21 actually caused by the UNbalanced Robertsonian translocation
- Down Syndrom due to effective \[partial\] trisomy 21 actually caused by the UNbalanced Robertsonian translocation
- Also considered more explicit: `GRCh38 (chr21q10;chr14q10):add` for this additional case
* This is a class of arm-fusion that is covered this way. Robertsonian is just one case.
​
* This is a class of arm-fusion that is covered this way. Robertsonian is just one case. ​
### Others
​
#### Isochromosome
​
* `GRCh38 (chrXq10;chrXq10),(chrXp:del)` - This one causes a form of Turner syndrome due to the _partial_ loss of the p-arm of chrX.
- The isochromosome `(chrXq10;chrXq10)` is two chrX q arms fused at the centromere. The p arms are lost [causing a form of Turner]
- A class. This is just an example that is connected to Turner syndrom as well as `GRCh38 (chrX:del)`
​
- The isochromosome `(chrXq10;chrXq10)` is two chrX q arms fused at the centromere. The p arms are lost \[causing a form of Turner\]
- A class. This is just an example that is connected to Turner syndrom as well as `GRCh38 (chrX:del)` ​
#### Ring chromosome
​
* `GRCh38 (chr14p;chr14q)` - Ring chromosome. The end of chr14 p arm is fused to the end of chr14 q arm.
- We need no further banding information for this since the other end is the p10 / q10 0-length "band" used for centromeric fusions.
- This ring chr14 is likely pathogenic for Epilepsy and mental retardation. Many ring chr have been encountered, with pathogenicities; although rare.
​
- This ring chr14 is likely pathogenic for Epilepsy and mental retardation. Many ring chr have been encountered, with pathogenicities; although rare. ​
### Not Actual Large-Scale Chromosomal Abberrations
​
#### Pathologic Repeats
Like Fragile X syndrome (a CGG repeat in 5' UTR of a certain chrX gene)
Express as a human genome variation.
Like Fragile X syndrome (a CGG repeat in 5' UTR of a certain chrX gene) Express as a human genome variation.
* In fact, many of these are already present in core CAR with CAids.
- Many of these https://genome.ucsc.edu/cgi-bin/hgc?hgsid=1586229845_vq7vMKDv7xneulmCWPuaUpQGa5je&db=hg38&c=chrX&l=147912009&r=147912238&o=147912048&t=147912050&g=clinvarMain&i=CGG ClinVar ids can be found in CAR. Not all.
- Many of these <https://genome.ucsc.edu/cgi-bin/hgc?hgsid=1586229845_vq7vMKDv7xneulmCWPuaUpQGa5je&db=hg38&c=chrX&l=147912009&r=147912238&o=147912048&t=147912050&g=clinvarMain&i=CGG> ClinVar ids can be found in CAR. Not all.
* Because it doesn't support cardinality in storage, CAR expands to an indel sequence (insert obviously). It has the clinvar for many Fragile X _premutatons_ (like 18 repeat copies, 37 repeat copies etc)
* But for Fragile X syndrome, problems arise with >200 repeat copies.
- These are not all in core CAR, even though the 201 ClinVar variant could be since expanded sequence is <10,000nt
- Doesn't work generically anyway for more copies or slightly longer repeat sequence.
* For which we have SV, specifically CNVs
- Express the repeat as a CNV.
- Do have to locate it. https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chrX%3A147912048%2D147912074&hgsid=1586229845_vq7vMKDv7xneulmCWPuaUpQGa5je
​
* `GRCh38 (chrX:147912050-147912052)x201` - Fragile X with likely pathogenic phenotype exhibited; https://www.ncbi.nlm.nih.gov/clinvar/variation/183387/?new_evidence=true
* `GRCh38 (chrX:147912050-147912052)x201,500` - Covering many/all observered likely pathogenic Fragile X CNV variants
​
- Do have to locate it. <https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chrX%3A147912048%2D147912074&hgsid=1586229845_vq7vMKDv7xneulmCWPuaUpQGa5je> ​
* `GRCh38 (chrX:147912050-147912052)x201` - Fragile X with likely pathogenic phenotype exhibited; <https://www.ncbi.nlm.nih.gov/clinvar/variation/183387/?new_evidence=true>
* `GRCh38 (chrX:147912050-147912052)x201,500` - Covering many/all observered likely pathogenic Fragile X CNV variants ​
#### Structural Variants
While some can be large scale, can be expresseds as regular SV using genomic coordinates.
* https://genboree.org/genboreeKB/projects/clingen-allele-registry/wiki/Observations_from_Gnomad_VCF#D1-Obvious-SV-Cases-38-Syntax
* <https://genboree.org/genboreeKB/projects/clingen-allele-registry/wiki/Observations_from_Gnomad_VCF#D1-Obvious-SV-Cases-38-Syntax>
* Translocations.
* Inversions.
* Large Deletions.
......