Case T arr [GRCh37] 1q22 - PowerPoint Presentation

1. Case Tarr[GRCh37] 1q22(155887333_156224120) x3Newborn with unspecified brain malformationNote: 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.

2. Clinical Informationarr[GRCh37] 1q22 (155887333_156224120) x3Newborn with an unspecified brain malformationUse the GAIN scoring metric

3. Section 1: Initial Assessment of Genomic ContentCase TGenes InvolvedWould apply category 1A (contains protein-coding or other known functionally important elements), as this duplication involves several protein-coding genes.0 points; continue evaluationTotal: 0 points

4. Section 2: Overlap with Established TS, HI, or Benign Genes/Genomic RegionsCase TClinGen Curated Track: EmptyCNV T does not overlap with any established HI, TS, or benign genes/gnomic regions. Section 2 is n/a.Total: 0 points

5. Section 3: Evaluation of Gene NumberCNV S contains 16 protein-coding genes (Category 3A: 0 points).Total: 0 points

6. PubMed search for “1q22 duplication”Sowinska-Seidler et al. 2018 (PMID:29845577) describe a male child with metopic and unilateral lambdoid synostosis, muscular hypotonia, developmental delay, and dysmorphic features.De novo 1.26 Mb duplication at 1q22q231 identifiedOnly other testing reported on the proband was a 550 band karyotypeAuthors proposed that overexpression of LMNA and BGLAP, two genes involved in osteoblast differentiation, may be involved in the phenotypeThese two genes are included in CNV TThe authors showed increased expression of each in patient-derived blood samples as compared to controls, but no other functional studies were performed to validate the claim that this contributes to the craniosynostosis phenotype.Section 4: Detailed Evaluation of Genomic Content

7. 1q22 duplication search, continuedFichera et al. 2014 (PMID: 25540671)Describe a family with a 290 kb duplication at 1q22 segregating with behavioral problems with or without intellectual disability2 adult family members also displayed symptoms of inflammatory diseasePrevious testing on the proband included karyotype, Fragile X testing, and screening for neurometabolic disordersSubsequent family members only tested for the presence/absence of the duplication

8. Case TFichera et al. familySoinska-Seidler et al. dn

9. Assessing the informationThe phenotypes presented in Fichera et al. and Sowinska-Seidler et al. are seemingly disparate.Should this count as negative evidence?No. The variant observed in Sowinska-Seidler is much larger than CNV T or the variant observed in Fichera et al. Even though all 3 variants overlap, the seemingly disparate phenotype could be due to the additional genomic content duplicated in the larger variant.It is also possible the phenotypes reported in Fichera and/or Sowinska-Seidler are not related to the observed duplications, given the genetic heterogeneity associated with both neurodevelopmental disorders and craniosynostoses, and the relatively limited testing done on each proband.At best, the Fichera family (the CNV closest in size to CNV T) can be scored 0.30 points for 6 segregations (Category 4G).Also evaluate the individual genes within the CNV for evidence of triplosensitivity.Total: 0.30 points

10. Which genes should we focus on first?4 genes in the region are OMIM Morbid – let’s investigate them further.

11. Though this condition is AR, our patient was referred for unspecified brain malformation. This entry is designated with a “?,” meaning that the relationship between this gene and that disease presentation is provisional. OMIM documents a single report of 2 brothers in a consanguineous family with this phenotype and a frameshift variant in this gene identified on exome sequencing.This is not convincing evidence, but it may be something to monitor over time, if the patient’s phenotype is consistent.

12. Are any of these AD disorders caused by triplosensitivity?Literature review for triplosensitivity evidence for these genes and others in the region was uninformative as of August 2020.Evaluated by ClinGen Dosage Sensitivity in 2016; TS score 0

13. Population DataApproximate length of CNV TNo relevant population variants in gnomAD SV as of August 2020.

14. Population DataDGV Gold Standard Track: EmptyNo relevant population variants in the DGV Gold Standard dataset as of August 2020.

15. Section 5: Evaluation of Inheritance Pattern/Family History for Patient Being StudiedOur patient is a newborn with a brain malformation.There has been a one report of a similarly-sized CNV segregating with neurodevelopmental phenotypes in a single family.Uncertain if this variant is the cause of the neurodevelopmental disorders in this family.Even if it was, given that it was a single family, the phenotypic spectrum may not be completely described.No other phenotypes were reported to us for our patient, and, since they are a newborn, it is uncertain what additional phenotypes may manifest as they are older.The inheritance of this variant is unknown in our patient.In the setting of so much uncertainty, utilize category 5F, inheritance information is unavailable or uninformative, 0 points.Total: 0.30 points

16. ConclusionClassification: Variant of Uncertain SignificanceAdditional evidence is necessary to clarify the role of similar duplications in disease.