Evaluation of the X-chromosome inactivation patterns in females with Gabriele-de Vries syndrome and expansion of clinical spectrum

Gabriele-de Vries syndrome (GDVS) is a syndromic form of intellectual disability caused by pathogenic variants in the YY1 gene, which encodes a ubiquitously expressed transcription factor that plays a crucial role in the X-chromosome inactivation (XCI) process. Recent studies have implicated de novo YY1 pathogenic variants in skewed XCI in females with GDVS. Here, we report clinical and molecular features of 11 GDVS patients (ten females), including eight newly identified cases, two being a familial case. Patients exhibited the core phenotype of GDVS but with notable clinical heterogeneity, displaying additional features such as autism spectrum disorder, thyroid dysfunction, hearing impairment, and dysarthria. We also discuss thyroid and other endocrine alterations, autoimmune conditions, and movement disorders in GDVS. Eight YY1 variants were analyzed in silico , exhibiting high pathogenicity scores and predicted structural or functional impact, with most affecting DNA binding or zinc finger domain interactions. Finally, we investigated the XCI patterns of ten female patients, and XCI skewing (moderate or extreme) was detected in blood samples from all of them. Our findings expand the clinical and molecular spectrum of GDVS, in addition to reinforcing a potential involvement of YY1 mutations in modulating XCI patterns in females.