POGZ

Inheritance Pattern: AD

Disease ID:MONDO:0014606

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014606

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014606

Submitter: Illumina

The POGZ gene is located on chromsome 1 at 1q21.3 and encodes the pogo transposable element derived with ZNF domain protein. The complete function of this protein have not yet been characterized, but it is known to play a role in mitosis, including kinetochore assembly and cohesion of sister chromatids. It has also been proposed to function in chromatin remodelling. POGZ was first reported in relation to autosomal dominant neurodevelopmental disorders in 2012 (22495311: Neale et al. 2012). At least 50 unique variants, including frameshift, stop-gained, splice, and missense variants, have been reported in humans (26942287: Stessman et al. 2016). POGZ-related neurodevelopmental disorders include autism spectrum disorder, intellectual disability, and White-Sutton syndrome, which includes additional features of obesity tendency, hypotonia, microcephaly, feeding problems, visual impairment, and characteristic facial features. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included seven cases from three publications (25533962: Deciphering Developmental Disorders Study 2015; 26739615: White et al. 2016; 26942287: Stessman et al. 2016). In many cases, variants were confirmed to have occurred de novo. Predicted null or truncating variants are most common, but a smaller number of missense variants have also been reported. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease in haploinsufficiency. This gene-disease relationship is supported by the gene's expression in the brain, where it localizes to neuronal nuclei and chromosomes; disrupted DNA binding activity by a missense variant in vitro; and impaired non-associative learning in a Drosophila knockdown model (27103995: Matsumura et al. 2016; 26942287: Stessman et al. 2016). In summary, POGZ is definitively associated with autosomal dominant POGZ-related neurodevelopmental disorders. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

Inheritance Pattern: AD

Disease ID:MONDO:0014606

Submitter: ClinGen

*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.

Inheritance Pattern: AD

Disease ID:MONDO:0014606

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0014606

Submitter: Orphanet