ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
27148570 In Ye Y et al 2015, they had 7 patients with developmental delay and microcephaly, and de novo loss-of function mutations in POGZ were detected by whole-exome sequencing in 6 of the patients. Four of the patients had frameshift mutation, one patient had nonsense mutation, and another one had a heterozygous deletion of exons 4-19. All of these variants were predicted to cause loss of function.
26942287 In Stessman et al 2016, they collected clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 patients with neurodevelopmental disorders (intellectual disability and autism spectrum disorders primarily). All of the variants were de novo, either frameshift or nonsense mutations. They concluded that the dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm.
26739615 White et al 2016. They identified de novo heterozygous truncating variants in POGZ in 5 unrelated individuals. Careful review of the phenotypes revealed shared features that included developmental delay, ID, hypotonia, behavioral abnormalities and similar facial characteristics. Variable features included short stature, microcephaly, strabismus and hearing loss. They suggested that loss of function variants in POGZ lead to an identifiable syndrome of neurodevelopmental disorders with specific phenotypic traits.

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.