Evaluation of Genomic Content in a 3-Month-Old Male with Intractable Seizures
This case involves a 3-month-old male with intractable seizures, analyzed for a de novo duplication in chromosome 11p11.2. The evaluation includes assessment of protein-coding genes, overlap with established syndromes, gene number, and detailed genomic content review, providing insights for clinical diagnosis and management.
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Case Q arr[GRCh37] 11p11.2 (43983424_46063424) x3 dn 3-month-old male with intractable 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] 11p11.2(43983424_46063424) x3 dn 3-month-old male with intractable seizures De novo Use the GAIN scoring metric
Section 1: Initial Assessment of Genomic Content Case Q Genes Involved 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
Section 2: Overlap with Established TS, HI, or Benign Genes/Genomic Regions CNV Q overlaps several entries in the ClinGen curated track, including: Potocki-Shaffer syndrome region ALX4 EXT2 Note that each of these entries are red, indicating that they have a HI score of 3. TS score for each = 0 CNV Q completely encompasses ALX4 and EXT2 no reason to believe this gain is acting as LOF No category in Section 2 applies Case Q ClinGen Curated Track Total: 0 points
Section 3: Evaluation of Gene Number CNV Q contains 17 protein-coding genes (3A, 0 points). Total: 0 points
Section 4: Detailed Evaluation of Genomic Content 11p11.2 duplications As of July 2020, literature review does not return any relevant information about gain of 11p11.2 (only) Gene-level evaluation OMIM-Morbid Genes: ALX4 ClinGen TS=0 EXT2 ClinGen TS=0 PEX16 Peroxisomal biogenesis disorders (AR) PHF21A ClinGen TS = 0 SLC35C1- Congenital disorder of glycosylation (AR) MAPK8IP1 susceptibility to noninsulin-dependent diabetes mellitus As of July 2020, literature review does not return any relevant information regarding whole- gene duplications of these genes. Case-control CNV Q is very similar in size/genomic content to the Potocki-Shaffer region, a well-studied microdeletion syndrome. Check case-control studies for data on the reciprocal duplication. Total: 0 points
Case-Control Studies Case Q There are some overlapping duplications in the case cohort of the Coe et al. 2014 case-control study, but none in the controls. Let s look at the data in more detail. Coe et al. CASES Coe et al. CONTROLS
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 Q Duplications were observed in 2 cases referred for clinical microarray testing, and in 0 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 Case Q DGV Gold Standard Data No overlapping cases in the DGV Gold Standard Data Set. Total: 0 points
Population Data No relevant variants in gnomAD SV. Approximate area of CNV Q Total: 0 points
Section 5: Evaluation of Inheritance Pattern/Family History for Patient Being Studied Our patient is a 3-month-old with intractable seizures. The variant is de novo. No information is provided about the parents. No particular phenotype has been reported in association with this duplication, or with similar duplications. Use category 5F even though the variant is de novo, in this particular instance, this information is uninformative (0 points). Total: 0 points
Conclusion Classification: Variant of uncertain significance There is no evidence to support or refute a role for this particular duplication in disease. Would recommend additional testing to investigate other potential genetic causes for this patient s intractable seizures.
