Transcriptome analysis of patients with loss-of-function POGZ variants in four unrelated Chinese families.

Intellectual disability (ID) and autism spectrum disorders (ASD) are complex neurodevelopmental disorders (NDDs) with a strong genetic component, and recent studies have highlighted the POGZ gene on chromosome 1q21.3 as a significant contributor, particularly linked to White-Sutton syndrome (WHSUS). POGZ-associated disorders are most commonly caused by heterozygous loss-of-function (LOF) variants, frequently arising de novo. In this study, we aimed to further this understanding by exploring novel pathogenic variants in the POGZ gene and their impact on the molecular landscape of NDDs. We conducted whole-exome sequencing (WES) in four unrelated Chinese families, each with a member diagnosed with ID. Four heterozygous LOF variants in POGZ were identified, including two frameshift deletions, one canonical splice-site substitution, and one nonsense variant. Parental testing was partially available for three probands and, in each case, was consistent with a de novo origin; parental data were unavailable for the remaining proband. Three out of the four LOF variants identified in this study are novel. Additionally, we undertook RNA sequencing and cohort analysis to delve into the molecular implications of POGZ haploinsufficiency. Aberrant expression was observed in 484 genes across the patients, a subset of which are involved in synaptic formation and function, offering insights into the involved molecular mechanisms. This study broadens the mutational spectrum of POGZ-related NDDs and underscores the crucial role of heterozygous POGZ LOF variants in the pathogenesis of ID and related conditions.