A novel gain of function variant in NUAK2 causes oculomotor apraxia in a three-generation family

Oculomotor apraxia (OMA) is a condition involving impaired voluntary initiation of rapid horizontal eye movements with a broad aetiology. Congenital OMA is associated with structural brain differences, cerebellar ataxia, and neurodevelopmental differences. Although pathogenic variants in numerous genes have been identified, many cases lack a confirmed genetic cause. This study describes a three-generation family with autosomal dominant congenital OMA and cerebellar vermis hypoplasia. Affected members include an 8-year-old proband, his father, and paternal grandmother, all sharing non-progressive OMA confirmed on MRI. Additional features include autism spectrum disorder, developmental delay, and patellofemoral dysplasia in some members. Re-analysis of exome data and confirmation by genome sequencing, identified a heterozygous missense variant in NUAK2 (c.504G > C, p.Gln168His) segregating across all three generations. NUAK2 encodes a kinase involved in neurodevelopment; previously, reported loss-of-function variants have been linked with neural tube defects. Functional studies suggest that this variant produces a gain-of-function, elevating catalytic activity nearly two-fold compared to wild-type. This is the first report implicating NUAK2 gain-of-function in OMA, suggesting that both increased and decreased NUAK2 kinase activity could result in distinct neurodevelopmental phenotypes. Further studies are needed to clarify the role of NUAK2 in cerebellar development and pathogenicity.