Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder.

WAPL deficiency causes a developmental disorder with phenotypes linked to 10q22.3q23.2 deletions, establishing WAPL as a key driver gene in this region.

• Why it matters: Understanding the genetic basis of cohesin-related disorders is crucial because it reveals how chromosome architecture influences development and disease, filling a gap in knowledge about cohesin release factors.
• What they did: The study analyzed individuals with damaging variants in WAPL, PDS5A, and PDS5B, modeled WAPL deficiency in human cells and mice, and used CRISPR to generate variants, revealing dosage effects and gene expression overlaps.
• The result: Findings demonstrate WAPL haploinsufficiency causes developmental issues, with dosage thresholds impacting viability, and position WAPL as a central gene in the 10q disorder region, advancing insights into cohesinopathies.