Monoallelic loss-of-function variants in ZNF536 are associated with a neurodevelopmental disorder with prominent behavioral features.

Monoallelic loss-of-function variants in ZNF536 are linked to a neurodevelopmental disorder with autism, behavioral issues, and developmental delays in humans and mice.

• Why it matters: Understanding the genetic basis of neurodevelopmental disorders can improve diagnosis and inform potential interventions. Rare protein-altering variants in ZNF536 had not been systematically studied in this context.
• What they did: An international cohort of 21 affected individuals with 18 unique heterozygous ZNF536 variants was assembled, with most variants predicted to be loss-of-function and often de novo; functional studies used a Zfp536 p.Gln169Ter knock-in mouse model.
• The result: Heterozygous mice exhibited autism-like behaviors, increased anxiety, and brain structural abnormalities, supporting that monoallelic LoF variants in ZNF536 contribute to a dosage-sensitive neurodevelopmental disorder in humans.