White-Sutton syndrome (WHSUS) is a rare neurodevelopmental disorder due to pathogenic variants in the POGZ gene. Its phenotype includes developmental delay, behavioral dysfunctions, hypotonia, and dysmorphic features. The condition is still poorly known: comprehensive clinical descriptions and exhaustive genotype-phenotype correlations are lacking, limiting diagnostic and therapeutic advancements. Here, we report molecular, clinical, and instrumental data from the first and largest Italian cohort (19 patients). Our results highlight the importance of an extensive approach at the time of diagnosis-including early nutritional support for preventing obesity-related complications and instrumental screening for congenital malformations. Preliminary data suggest that splicing variants could be associated with more severe phenotypes. This study provides valuable new insights into WHSUS and represents a significant step towards its comprehension.

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.

White-Sutton syndrome (WSS), associated with POGZ gene mutations, is a rare genetic disorder characterized by a spectrum of phenotypic features, including intellectual disabilities, developmental delays, and epilepsy. A case report described a female patient diagnosed with WSS who experienced seizures resistant to conventional antiseizure medications. Despite various therapeutic attempts, including valproate, topiramate, levetiracetam, clobazam, rufinamide, and vigabatrin, the patient's seizures persisted. After initiating an off-label treatment with cannabidiol (CBD), the patient achieved complete remission from seizures. Following significant clinical improvement, CBD therapy was discontinued by the parents against medical advice, leading to seizure recurrence. Upon reinstatement of CBD, the patient once again experienced successful seizure control. This report emphasizes the need for further investigation into the off-label use of CBD, as an adjunctive therapy in pediatric individuals with drug-resistant epilepsy associated with WSS. Although CBD shows promise in other epileptic syndromes, this case highlights its potential effectiveness in this specific condition. This manuscript aims to contribute to the understanding of WSS and advocate for further research into novel treatments, particularly the role of CBD in managing epilepsy within this complex clinical context.

Novel denovo variants of exome sequences are major cause of pathogenic neurodevelopmental disorders with a dominant genetic mechanism that emphasize their heterogeneity and complex phenotypes. White Sutton syndrome and Gabriele-de-Vries syndrome are congenital neuro-impairments with overlap of severe intellectual disability, microcephaly, convulsions, seizures, delayed development, dysmorphism of faces, retinal diseases, movement disorders and autistic traits. POGZ gene codes for pogo transposable element-derived zinc-finger protein and YY1 gene regulates transcription, chromatin, and RNA-binding proteins that have been associated with White Sutton and Gabriele-de-Vries syndromes, in recent data. We present probands of two unrelated consanguineous families with complicated, unexplained neurocognitive syndromic characteristics clinically undiagnosed. Objectives of the study were to identify altered genetics and protein characteristics underlying molecular pathological pathways in both the patients. Whole exome sequencing identifies novel, denovo missense variant NM_015100.4: c.776 C>T (p. Pro259Leu) in exons 19 of POGZ gene and non-frameshift variant NM_003403.5: c.141_143delGGA (p. Glu47del) in exon 1 of YY1 gene for White Sutton syndrome in eight years five-month-old girl and Gabriele-de-Vries syndrome in seven years eight months old boy residing in Rawalpindi and Chakwal districts of Punjab, Pakistan respectively. Protein modelling for identified variants predicts size and conformation modifications in mutated amino acid residues that lead to damaging effects in the conserved domains expressed as neurological pathophysiology. The present study widens the diversely ethnic and highly inbred gene pool of Punjab, Pakistan population for spontaneously originated deleterious mutations and contributes to the continuously expanding phenotypic canvas. Molecular genetic identification and personalized diagnosis for the patients suffering from complicated neurodevelopmental phenotypes, for better care, management of day-to-day activities and prolonged life span are the utmost hopes.

White-Sutton syndrome (WHSUS) is a rare neurodevelopmental disorder caused by heterozygous variants in the POGZ gene. With slightly over 100 reported cases, the diagnosis of WHSUS remains challenging due to its variable and non-specific clinical features. We report a novel case of WHSUS carrying a heterozygous de novo variant in the POGZ gene and with characteristic clinical features including global developmental delay, autism spectrum disorder, generalised myoclonic epilepsy, hypotonia and distinct dysmorphic features. Notably, the patient also presented with mild gastrointestinal symptoms and was diagnosed with celiac disease (CD) based on elevated tissue transglutaminase IgA levels, confirmatory duodenal biopsy and HLA typing. Based on the recent evidence implicating chromatin remodelling genes in CD and the known role of the POGZ protein as a regulator of chromatin remodelling, we cautiously propose, for the first time, to our knowledge that the POGZ gene may contribute to the pathogenesis of the celiac disease, providing evidence of a possible association between White-Sutton syndrome and CD. Comprehensive functional, genetic and epidemiological studies are needed to explore further this potential association, which may broaden the clinical spectrum of WHSUS and improve the understanding of CD-related epigenetic factors.