1286410114983330x1 2 year old male with developmental delay and seizures Note These example CNVs have been created for educational purposes in order to ensure that each evidence type in the scoring matrices are utilized across the entire set no single CNV will necessarily cover all evidence t ID: 931699
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Slide1
Case Aarr[GRCh37]12p13.1p12.3(12864101_14983330)x1
2 year old male with developmental delay and seizures
Note: These example CNVs have been created for educational purposes in order to ensure that each evidence type in the scoring matrices are utilized across the entire set (no single CNV will necessarily cover all evidence types). These are not actual CNVs that have been observed in a laboratory setting. As such, please evaluate the coordinates as given, regardless of other considerations that may apply in the actual clinical laboratory setting. For example, if your CNV is below the size cutoff your laboratory uses on a daily basis, please disregard this for the sake of this exercise and evaluate the content within the provided coordinates. Assume that the CNV is technically valid.
Slide2Clinical Information
arr[GRCh37]12p13.1p12.3(12864101_14983330)x12 year old male with developmental delay and seizuresInheritance is unknownUse the LOSS scoring metric
Slide3Section 1: Initial Assessment of Genomic Content
Would apply category 1A (contains protein-coding or other known functionally important elements), as this deletion includes several protein-coding genes.0 points; continue evaluation
Total: 0 points
Case A
Genes contained
Slide4Section 2: Overlap with Established/Predicted HI or Established Benign Genes/Genomic Regions
Complete loss of
GRIN2B
, known HI gene
Slide5https://dosage.clinicalgenome.org
Slide6Date last evaluated: September 25, 2019
Total: 1 point
Slide7Classification: Pathogenic
At this point, because we know this deletion completely overlaps a known dosage sensitive gene, we can apply category 2A (1 point)Even though GRIN2B also has gnomAD pLI/LOEUF and DECIPHER HI scores that could warrant application of category 2H, we will not ALSO apply this, because it would be double counting
We already
know
that
GRIN2B
is haploinsufficient given the abundance of case-level evidence; we should not assign additional points for being
predicted haploinsufficient
Though the classification of the CNV has been made, it is still worthwhile to look at the other genes in the region to determine if there is other relevant information to report.For the purposes of this example, we will also walk through the remaining sections of the metric.
Slide8Section 3: Evaluation of Gene Number
c
Category 3A: 0-24 genes, 0 points
Slide9Section 4: Detailed Evaluation of Genomic Content
Since GRIN2B is a known HI gene, there is no need to collect additional case-level evidence to further support this gene.However, let’s take a look at the following:Other genes in the region – is there anything else we should be mentioning in our report?
Population data - make sure there is no contradictory information.
Slide10Are there any other genes of potential relevance for the report?
Review these for inheritance, mechanism
Slide11Evidence comes from a single family – questionable.
Brackets around the phenotype indicate “
nondisease
” (e.g., apparently abnormal lab test values)
Potentially relevant,
investigate further
Slide12CDKN1B
Variants in this gene have been associated with a multiple endocrine neoplasia-like syndrome (“MEN4,” per OMIM).Characterized by acromegaly, primary hyperparathyroidism, and multiple endocrine and/or gastro-entero-pancreatic tumorsOnset typically in adulthood
Autosomal Dominant
As of March 2020, this gene has not been formally evaluated by ClinGen for Dosage Sensitivity
Gene-Disease Validity: “Definitive” for MEN4
Reports of putative LOF variants in individuals with MEN4 phenotype
PMIDs: 30990521, 17519308, 17030811, 24819502, 29036195, etc.
Worth mentioning in the report
Potential for future screening for proband
Slide13Numerous small DGV gold standard variants throughout the region. Nothing approximating the loss of this entire region. Let’s look closer at the variants within
GRIN2B.
Population Data: DGV Gold Standard
Slide14The DGV Gold Standard variants within
GRIN2B all appear to be intronic. These are unlikely to result in loss of
GRIN2B
function, and do not contribute contradictory evidence to our case.
Slide15Population Data: gnomAD SV
15.7 Mb Inversion
No
pLOF
structural variants involving
GRIN2B
No other significant/relevant population variants in this region.
Slide16Section 5: Evaluation of Inheritance Pattern/Family History for Patient Being Studied
CNV is pathogenic regardless of patient’s presentation due to complete loss of a known HI gene, GRIN2BIn this example, however, your patient’s phenotype is non-specific (developmental delays and seizures) but consistent with what has been reported for this geneThough it is not necessary, category 5G could be applied, even though inheritance information is not available for your particular case.
Slide17ConclusionFinal points based on publicly available evidence: 1.0
Classification: PathogenicClassification is driven by the complete loss of GRIN2B, a known HI geneWorth noting the complete loss of CDKN1B
, a gene associated with a tumor predisposition syndrome. Evidence suggests LOF is a potential
disease mechanism.