Genotype-Phenotype Comparison in POGZ-Related Neurodevelopmental Disorders by Using Clinical Scoring

Background: Pathogenic variants in POGZ cause White–Sutton syndrome, characterized by intellectual disability (ID), developmental delay, autism spectrum disorder, short stature, and distinct facial features. This study collected clinical data on previously unreported individuals with POGZ variants and performed a large-scale genotype–phenotype analysis using a clinical scoring system. Methods: We gathered clinical information on new patients and combined it with published cases (total n=65). A scoring method was developed to quantify phenotypic severity. Results: The analysis revealed that truncating variants in POGZ (predicted loss-of-function) generally led to more severe phenotypes (higher scores) compared to missense variants or mosaic cases. Recurrent truncating variants in exon 15 were associated with particularly high clinical severity scores. Conclusions: This genotype–phenotype comparison underscores that loss-of-function variants in POGZ lead to a recognizable syndrome of neurodevelopmental disorder with specific clinical features. The clinical scoring approach may aid in predicting phenotypic severity based on variant type in POGZ-related White–Sutton syndrome.