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

ZNF536

Haploinsufficiency of ZNF536, a C2H2 zinc-finger transcriptional repressor acting as a dosage-sensitive regulator of cortical development

An international collaboration assembled 21 affected individuals carrying 18 rare heterozygous protein-altering ZNF536 variants, 15 of 18 being predicted loss-of-function alleles. Among the 17 families with inheritance data, 12 variants arose de novo and 5 were inherited from mosaic or mildly affected parents. Affected individuals showed developmental delay with high rates of autism spectrum disorder, intellectual disability, hyperactivity, aggressive behaviour, anxiety and hyperphagia, and frequent epilepsy and sleep disturbances. A Zfp536 p.Gln169Ter knock-in mouse was non-viable when homozygous, while heterozygotes displayed autism-like behaviours, increased anxiety and impaired recognition memory, with reduced cortical size, cortical thickness and deep-layer neuronal density in the embryonic brain. The pathogenicity of missense variants remains to be determined.

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

This is a well-executed first description: a 21-case cohort, an excess of de novo variants, and a mouse model consistent with a previously published knockout. ZNF536 is already captured by any exome or genome, so the bottleneck is annotation rather than access to the target: a de novo truncating variant in this gene now becomes interpretable in a neurodevelopmental disorder with behavioural dysregulation. The caveat concerns missense variants, whose pathogenicity is unresolved — caution is warranted before calling an isolated missense variant.

Analysis by Dr Thibaut Benquey