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

WAPL haploinsufficiency (cohesin release factor) with a dosage-sensitivity threshold

Cohesin release factors (WAPL, PDS5A, PDS5B) had never been tied to Mendelian disease. By phenotyping 27 individuals with damaging WAPL variants, modeling WAPL deficiency in human cells and mice, and aggregating consortium data, the authors define a WAPL-related disorder featuring developmental delay, intellectual disability and further developmental anomalies. WAPL is nominated as a driver gene of the recurrent 10q22.3q23.2 genomic disorder region. iPSC/CRISPR and mouse models reveal a dosage-sensitivity threshold below heterozygosity, while PDS5A/PDS5B cohorts showed no specific phenotype.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A comprehensive clinical, cellular and murine effort that firmly anchors WAPL as a new cohesinopathy gene and clarifies a recurrent genomic disorder. For practice, the target is already captured by WES/WGS; the challenge is variant interpretation and recognizing the phenotypic overlap with the 10q deletion. The dosage-threshold concept is useful for counseling.

Analysis by Dr Thibaut Benquey