ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
24033328 In 2014, Chassaing et al. used direct sequencing and PCR on 150 individuals with anophthalmia and microphthalmia (AM) to identify variants in 7 genes related to AM including GDF6, FOXE3, PAX6, RAX, SOX2, VSX2, and OTX2. Analysis identified variants in OTX2 in 5 individuals. Variants identified in OTX2 include 2 nonsense variants, 1 frameshift variant, and 2 deletions including the OTX2 gene (coordinates not provided). The frameshift variant, 1 nonsense variant, and 1 deletion were familial cases (inherited from a symptomatic parent), while 1 deletion variant and 1 nonsense variant were of unknown inheritance (parents were not available for study, but no family history reported).
19956411 In 2009, Henderson et al. used microarray and PCR on 142 patients with either Leber congenital amaurosis (LCA) or early onset retinal dystrophy (EORD). Analysis identified a de novo nonsense variant (c.413C>G p.S138X) in an individual with EORD. Of note, the proband also had a pituitary insufficiency.
18781617 In 2008, Wyatt et al. used PCR, Multiplex Ligation-Dependent Amplification (MLPA), FISH, and oligo array-CGH on 165 individuals with anophthalmia, microphthalmia, or coloboma to identify potential variants in OTX2. The authors identified OTX2 variants in 8 individuals. Probands 1 and 2 had deletions encompassing the whole OTX2 genes and other genes. Proband 3 had a de novo nonsense variant in the first exon of OTX2 predicted to result in nonsense-mediated decay. Individuals 4 and 5 were siblings with the same frameshift variant predicted to cause nonsense-mediated decay. This variant was absent in their parents. Individuals 6 and 7 were dizygotic twins with a nonsense variant found in their father with reduced vision in a single eye. Proband 8 was found to have a frameshift variant which was also present in their unaffected mother.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.