Submission Details

POGZ was first reported in relation to autosomal dominant White-Sutton syndrome (also known as intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome) in 2016 (White et al., PMID: 26739615). White et al. described five individuals with similar phenotypes, all of which had predicted loss-of-function (LoF) variants in POGZ. All individuals had a broad spectrum of intellectual disability/developmental delay with or without autism, and characteristic facial features. At this time, 59 pathogenic/likely pathogenic variants have been reported in humans, with all but one less than 51 bp.

Most reported variants are frameshift or nonsense variants predicted to lead to LoF. All are de novo or assumed de novo (where DNA from one parent may not be available). With the expanding phenotypic spectrum (for example Batzir et al. 2020, PMID: 31782611), it is highly likely that more cases of White-Sutton syndrome, caused by pathogenic variants in POGZ, will be reported.

Non-human model organisms have been used to investigate the effect of POGZ LoF. Two such examples are included in this curation: a Drosophila model (Stessman et al., PMID: 26942287) and a KO mouse model (Suliman et al., 2018). Both supported an important role for POGZ in neuronal functioning, with an adverse behavioural phenotype presenting with POGZ LoF. Note that there was no PMID that could be found associated with the Suliman et al. paper (doi: https://doi.org/10.1101/437442). Based on the evidence presented in this paper, the default points for a non-human model organism (2 points) were awarded.

In summary, there is definitive evidence supporting the relationship between POGZ and autosomal dominant White-Sutton syndrome. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on March 9, 2020.

Variants in POGZ were first reported in association with White-Sutton syndrome (intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome) in 2016, at which time White et al. (PMID: 26739615) described five individuals with similar phenotypes, all of which had predicted LOF variants in POGZ. All individuals had a broad spectrum of intellectual disability/developmental delay with or without autism, and characteristic facial features. At this time, 59 pathogenic/likely pathogenic variants have been reported in humans, with all but one less than 51bp.

Variants in this gene have been reported in a number of individual probands since 2016. Most are predicted LOF, as duplications, deletions, or frameshift variants lead to a premature stop codon. All are de novo, or assumed de novo (where DNA from one parent may not be available). With the expanding phenotypic spectrum (for example, as explored in Batzir et al., PMID: 31782611), it is highly likely that more cases of White-Sutton syndrome, caused by pathogenic variants in POGZ, will be reported, maintaining the definitive status of this gene-disease association.

Non-human model organisms have been used to investigate the effect of POGZ LOF on brain function, and behaviours related to White-Sutton syndrome. In this curation, two such examples are presented: first, a Drosophila model from Stessman et al. (PMID: 26942287), and second, a KO mouse model from Suliman et al. (2018). Both supported an important role for POGZ in neuronal functioning, with an adverse behavioural phenotype presenting with POGZ LOF. Note that there was no PMID that could be found associated with the Suliman et al. paper (doi: https://doi.org/10.1101/437442). Based on the evidence presented in this paper, the default points for a non-human model organism (2 points) were awarded.

In summary, at present there is an abundance of evidence to support a definitive classification for this gene-disease relationship. Future recurations will likely continue to support this recently described syndromic condition.