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

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

• Why it matters: Understanding the genetic basis of neurodevelopmental disorders is crucial for diagnosis and potential interventions, especially for rare variants whose effects are not well characterized.
• What they did: The study identified 18 rare, heterozygous protein-altering ZNF536 variants in 21 affected individuals, most of which were de novo, and modeled their effects using a Zfp536 p.Gln169Ter knock-in mouse, revealing behavioral and brain structural abnormalities.
• The result: Findings demonstrate that ZNF536 haploinsufficiency leads to developmental delays, autism-like behaviors, and cortical abnormalities, highlighting ZNF536 as a dosage-sensitive regulator of brain development and a genetic contributor to neurodevelopmental disorders.