Submission Details

Autosomal dominant

09/14/2020

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.

25533962 26739615 26942287 20562864 27103995