White-Sutton Syndrome via the POGZ Gene

Intellectual Disability (ID) is a heterogeneous group of neurodevelopmental disorders, characterized by congenital limitation in intellectual functioning (intelligence quotient, IQ ≤70), and adaptive behavior. It is diagnosed in ~1–3% of the population before 18 years of age (American Association of Intellectual and Developmental Disabilities, AAIDD).

White-Sutton syndrome is a form of syndromic intellectual disability that leads to delayed psychomotor development, intellectual disability, seizures, sleep difficulties, autism, self-injurious behavior, short stature, microcephaly, brachycephaly, deafness, feeding difficulties, dysmorphic features including hypotonic facies, short philtrum, low-set and posteriorly rotated ears, and abnormalities of head, neck, skeletal, visual, cardiovascular, and gastrointestinal systems (The Deciphering Developmental Disorders Study 2015. PubMed ID: 25533962; Tan et al. 2016. PubMed ID: 26763879; Stessman et al. 2016. PubMed ID: 26942287).

Pathogenic variants ( primarily de novo) in the human “POGO Transposable Element with ZNF Domain” gene (POGZ) have been reported in several cases with White-Sutton syndrome (White et al. 2016. PubMed ID: 26739615). POGZ maps to chromosome 1q21.3 and consists of 18 coding exons that encode the 1410 amino acid polypeptide POGZ. POGZ contains a cluster of multiple C2H2-type zinc fingers, a centromere protein (CENP) B-like DNA-binding domain, and a DDE domain that might regulate gene expression (Stessman et al. 2016. PubMed ID: 26942287). POGZ, a heterochromatin protein 1α-binding protein, is involved in mitotic cell cycle progression, kinetochore assembly and mitotic sister chromatid cohesion and is hypothesized to function as a transcriptional regulator in molecular networks crucial for neuronal function (Nozawa et al. 2010. PubMed ID: 20562864; Tan et al. 2016. PubMed ID: 26763879). To date, apart from small frameshift deletions/duplications, missense and nonsense variants, one gross duplication and one gross deletion involving POGZ have been reported. The disease transmission pattern is autosomal dominant.

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 800 genes have been identified in individuals with ID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016. PubMed ID: 26503795). Analytical sensitivity should be high because most pathogenic variants reported within this gene to date are detectable by sequencing. To date, one gross deletion and one gross duplication involving POGZ have been reported.

This test provides full coverage of all coding exons of the POGZ gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).