Loss of ANK3 Function Causes a Recessive Neurodevelopmental Disorder with Cerebellar Ataxia

Abstract

BackgroundANK3 encodes ankyrin-G, a key scaffolding protein essential for neuronal function. While both monoallelic and biallelic ANK3 variants have been linked to neurodevelopmental disorders (NDDs), existing evidence for their pathogenicity and clinical correlation remains limited and heterogeneous.ObjectiveTo delineate the clinical features associated with biallelic ANK3 predicted loss-of-function (pLOF) variants.MethodsWe employed exome sequencing, Sanger validation, detailed clinical phenotyping, and extensive international data sharing to identify patients with biallelic ANK3 variants.ResultsWe describe five individuals from three unrelated consanguineous families with segregating homozygous ANK3 pLOF variants. These patients presented with a relatively consistent phenotype comprising developmental delay, intellectual disability, hypotonia, variable epilepsy, and cerebellar signs including ataxia, tremor, and dysarthria. Among the three patients for whom brain magnetic resonance imaging was available, cerebellar atrophy was observed, predominantly affecting the superior vermis and cerebellar hemispheres. These clinical findings align with murine models lacking the cerebellar ankyrin-G isoform, which similarly exhibit ataxic features and high cerebellar ANK3 expression.ConclusionOur findings support a recognizable NDD with non-progressive cerebellar ataxia linked to biallelic ANK3 pLOF variants. (c) 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.