POGZ – White-Sutton Syndrome

White-Sutton syndrome is an autosomal dominant neurodevelopmental disorder caused by heterozygous pathogenic variants in the POGZ gene, clinically defined by intellectual disability, global developmental delay, microcephaly, hypotonia, speech impairment, sensorineural hearing loss and characteristic brain imaging abnormalities (MONDO:0014606, POGZ).

Large-scale genotype–phenotype analyses have identified heterozygous de novo loss-of-function POGZ variants in 117 unrelated probands exhibiting consistent neurodevelopmental and dysmorphic features, including cortical and cerebellar atrophy, delayed myelination and brainstem hypoplasia (PMID:35052493).

Variants arise almost exclusively as de novo truncating mutations with occasional maternal inheritance confirmed in one multiplex family (n=1 affected relative) (PMID:34133408). The spectrum comprises nonsense, frameshift and splice‐site changes, as well as rare intronic variants (e.g., c.2546-20T>A) causing exon skipping and escape from nonsense-mediated decay (PMID:35396900).

To date, over 20 unique truncating variants and multiple missense alleles have been reported; a representative mutation, c.3801C>A (p.Cys1267Ter), has recurred in independent cohorts (PMID:26739615). Missense variants predicted to escape NMD cluster in the proline-rich domain, correlating with more severe phenotypes (PMID:35052493).

Functional studies demonstrate that POGZ haploinsufficiency disrupts mitotic chromosome segregation and neural progenitor proliferation. De novo ASD-associated POGZ mutations impair DNA-binding activity in vitro (PMID:27103995), and a heterozygous knock-in mouse model exhibits cortical network dysfunction and reversible social deficits, supporting a LOF mechanism (PMID:32103003).

Conclusion: The convergence of extensive de novo truncating variant data and robust functional evidence establishes a Strong clinical validity for POGZ in White-Sutton syndrome, guiding diagnostic sequencing, variant interpretation and therapeutic development.

References

• Genes • 2022 • Genotype-Phenotype Comparison in POGZ-Related Neurodevelopmental Disorders by Using Clinical Scoring. PMID:35052493
• Genome Medicine • 2016 • POGZ truncating alleles cause syndromic intellectual disability. PMID:26739615
• Journal of Molecular Psychiatry • 2016 • De novo POGZ mutations in sporadic autism disrupt the DNA-binding activity of POGZ. PMID:27103995
• Nature Communications • 2020 • Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes. PMID:32103003

Evidence Based Scoring (AI generated)