Case R arr [GRCh37] 7q11.23 - PowerPoint Presentation

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Case Rarr[GRCh37] 7q11.23(74962064_76662064) x3 mat

4-year-old female with short stature; mother with short stature

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] 7q11.23 (74962064_76662064) x3 mat4-year-old female with short statureMother also has short stature and carries the variantUse the GAIN scoring metric

Section 1: Initial Assessment of Genomic Content

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

0 points; continue evaluation

Total: 0 points

Case R

Genes Involved

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

ClinGen Curated Track

Case R

2 known recurrent regions: Williams syndrome and distal 7q11.23

CNV R overlaps with the 7q11.23 recurrent distal region.

As of July 2020, this region has been curated by ClinGen, but does not have either a HI or TS score of 3, which is why it does not appear in the UCSC ClinGen curated track.

Total: 0 points

Section 3: Evaluation of Gene Number

CNV R contains 18 protein-coding genes (3A, 0 points).

Total: 0 points

Section 4: Detailed Evaluation of Genomic Content

CNV R overlaps the 7q11.23 recurrent distal region, including the genes HIP1 and YWHAGAs of July 2020, this region has a TS score of 1.

Per coordinates provided, does not appear to overlap with the classic Williams syndrome region, which has a TS score of 3.

Assume for the purposes of this example that this has been confirmed, and that there are no technical reasons to be concerned that CNV R includes any part of the typical Williams region.

Let’s begin by evaluating the evidence documented in the ClinGen TS evaluation.

Distal 7q11.23 duplications

Ramocki et al. 2010 (PMID:21109226):Family 11: 3-month-old male with history of large posterior encephalocele, Chiari III malformation, hydrocephalusSmaller duplication identified (includes

HIP1

, but not

YWHAG

)

Paternally inherited

Father with history of spinal cord schwannomaFamily 12: 16-year-old male with history of bipolar disorder, ADHD, aggressive behaviorDuplication more typical in size, includes both HIP1 and YWHAGDuplication also observed in 5-year-old sister with history of speech delay, ADHD, and aggressive behaviorNot maternally inherited; father unavailable for testing (“in prison”)

Distal 7q11.23 duplications

Faundes et al. 2016 (PMID:27867344)16-year-old female with history of obesity, mild intellectual disability, aggressive behavior, ADHDMother said to have “lower IQ,” brother said to have bipolar disorder

Proband had array, karyotype, and Prader Willi testing

Duplication involving both

HIP1

and

YWHAG

; de novo

Case-Control Studies

Case R

Coe

et al.

CASES

Coe

et al.

CONTROLS

There is at least one duplication in the case cohort of the Coe

et al.

2014 case-control study that is completely contained within Case R. There look to be several duplications that overlap the segmental duplications within the controls. Let’s look at the data in more detail.

Segmental Duplications

Case-Control Studies

Note that the data from Coe et al. 2014 is in NCBI36/hg18; once lifted over, these coordinates are very similar to CNV R

Only 1 duplication was observed in a cohort of cases referred for clinical microarray testing, and none in controls

p-value is not significant

Confidence interval surrounding the likelihood ratio includes 1

Technically, there is no statistically significant difference between cases and controls. However, there are so few cases observed (in both the case and control group), this information is difficult to assess. Opting to not award any points for this information.

Total: 0 points

Population Data

There are a few small duplications within the DGV Gold Standard set, but all are much smaller than CNV R.Some are overlapping the segmental duplication region.Note data from Coe et al.

is included in DGV

None of this information is enough to rule CNV R out as a potential cause for Mendelian disease.

Case R

DGV Gold Standard Data

Total: 0 points

Population Data

Approximate area of CNV R

Nothing here to suggest that CNVs similar in size/genomic content to CNV R are present at high frequencies in the general population.

Total: 0 points

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

Our patient is a 4-year-old female with a history of short stature.The variant is inherited from her mother, who is also said to have short stature.Short stature is a generic, highly heterogeneous phenotype.

Only a few cases have been reported in the literature with similar variants, and the phenotype has included varied neurodevelopmental presentations.

Not enough information at this time to confirm that these variants are causative of any phenotype, let alone whether or not short stature is part of that phenotype.

Use category 5F – even though this variant is inherited from a family member with a similar phenotype, the information (in this context) is uninformative (0 points).

Total: 0 points

ConclusionClassification: Variant of Uncertain Significance

There is not enough evidence to support or refute a role for this particular duplication in disease. Would recommend additional testing to investigate other potential causes for tis patient’s short stature.