Neurocardiogenetics: Exploring the association of rare <i>RYR2</i> variants with neuropsychiatric disorders in general and disease populations

Overlapping neuropsychiatric and cardiac features in rare monogenic syndromes stem from shared gene expression. Pathogenic gain-of-function <i>RYR2</i> variants, leading to a lethal cardiac arrhythmia syndrome known as catecholaminergic polymorphic ventricular tachycardia (CPVT), have also been associated with neuropsychiatric disorders such as epilepsy, schizophrenia, and intellectual disability. Neuropsychiatric phenotypes have not been reported in patients with calcium release deficiency syndrome (CRDS), a recently described inherited arrhythmia disorder distinct from CPVT caused by loss-of-function <i>RYR2</i> variants. Whether there is a robust association between ultra-rare <i>RYR2</i> variants and neuropsychiatric phenotypes in large population databases and disease cohorts has not been determined to-date. Here, we explore the association of <i>RYR2</i> variants with neuropsychiatric disorders in 748,879 individuals from multiple biobanks, including 155,236 non-Europeans, and in neuropsychiatric disease cohorts. Our analyses suggest an association between <i>RYR2</i> variants and epilepsy, while links with other disorders were not robust. In this process, a previously uncharacterized <i>RYR2</i> variant (p.Y4962N) with conflicting reported pathogenicity was found to be associated with both cardiac and neuropsychiatric phenotypes. To better understand the potential impact of the variant, we further assessed its mechanistic impact and found that RyR2<i>-</i>p.Y4962N results in loss-of-function. Such a finding has not been reported previously in association with <i>RYR2</i> loss-of-function variants or CRDS. Altogether, our study expands our understanding of the involvement of <i>RYR2</i> variants in neurocardiac phenotypes in general populations and disease cohorts, which could enhance personalized medicine efforts by integrating cardiac and neuropsychiatric risk profiles.