Case A arr [GRCh37]12p13.1p12.3 - PowerPoint Presentation

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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.

Clinical Information

arr[GRCh37]12p13.1p12.3(12864101_14983330)x12 year old male with developmental delay and seizuresInheritance is unknownUse the LOSS scoring metric

Section 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

Section 2: Overlap with Established/Predicted HI or Established Benign Genes/Genomic Regions

Complete loss of

GRIN2B

, known HI gene

https://dosage.clinicalgenome.org

Date last evaluated: September 25, 2019

Total: 1 point

Classification: 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.

Section 3: Evaluation of Gene Number

c

Category 3A: 0-24 genes, 0 points

Section 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.

Are there any other genes of potential relevance for the report?

Review these for inheritance, mechanism

Evidence comes from a single family – questionable.

Brackets around the phenotype indicate “

nondisease

” (e.g., apparently abnormal lab test values)

Potentially relevant,

investigate further

CDKN1B

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

Numerous 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

The 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.

Population Data: gnomAD SV

15.7 Mb Inversion

No

pLOF

structural variants involving

GRIN2B

No other significant/relevant population variants in this region.

Section 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.

ConclusionFinal 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.