Case O arr [GRCh37] 4p16.1 - PowerPoint Presentation

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Case Oarr[GRCh37] 4p16.1(8952198_9486394)x3 dn

7-year-old male with lissencephaly

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 Informationarr[GRCh37] 4p16.1(8952198_9486394)x3

dn7-year-old male with lissencephalyVariant is de novoUse the GAIN scoring metric

Section 1: Initial Assessment of Genomic Content

Case O

Genes Involved

Would apply category 1A (contains protein-coding or other known functionally important elements), as this duplication includes protein-coding genes.

0 points; continue evaluation

Total: 0 points

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

Case O

ClinGen Curated Track = EMPTY

Segmental Duplications

CNV O does not overlap with any current ClinGen curated genes/regions. Note that it does fall within a cluster of segmental duplications.

Total: 0 points

Section 3: Evaluation of Gene Number

Technically, CNV O contains 22 protein-coding genes.

HOWEVER, many of these genes are within the same family (ubiquitin specific peptidase 17 like family).

None of these genes have been associated with disease, so would only count them as 1.

Regardless, this still falls within Category 3A, 0 points.

Total: 0 points

Section 4: Detailed Evaluation of Genomic Content

As of July 2020, DEF31B1, FAM90A26, and the genes in the UPS17L gene family have not been associated with human disease per OMIMBasic literature search does not reveal any convincing evidenceCNV O was located in a cluster of segmental duplicationsCheck for evidence of population variation.

Approximate length of CNV O

DEF31B1

FAM90A26

These three variants are similar in size and genomic content to CNV O. What are their frequencies?

These variants have been observed on 1168, 1122, and 645 alleles, respectively (out of ~21,000 alleles). Their allele frequencies range from 3.0% to 5.4%.

All 3 variants have passed quality filters

For each variant, a sufficient number of alleles has been studied (>2000 alleles from a continental population).

While these variants have been observed within most of the studied populations, they are the most frequent in Africans, with an allele frequency between 6.5-11.5%.

This is too high to be a plausible cause for a rare anomaly such as lissencephaly.

Apply Category 4O, -1 points

Total: -1 points

Section 5: Evaluation of Inheritance Pattern/Family History for Patient Being Studied

Our patient is a 7-year-old male with lissencephalyRegardless of inheritance information, similar duplications are observed frequently in the general population, at frequencies too high to be a plausible cause for this phenotype.The variant is de novo.This does not change the evidence discussed above, or our assessment of the variant. No positive points should be awarded for this fact.

Total: -1 points

ConclusionClassification: BenignSimilar duplications are observed in the general population at frequencies too high to be a plausible cause for lissencephaly.

Consider additional testing to investigate other potential causes for lissencephaly in this individual.