De novo FRMD5 Missense Variants in Patients with Childhood‐Onset Ataxia, Prominent Nystagmus, and Seizures

Background FRMD5 variants were recently identified in patients with developmental delay, ataxia, and eye movement abnormalities. Objectives We describe 2 patients presenting with childhood‐onset ataxia, nystagmus, and seizures carrying pathogenic de novo FRMD5 variants. Weighted gene co‐expression network analysis (WGCNA) was performed to gain insights into the function of FRMD5 in the brain. Methods Trio‐based whole‐exome sequencing was performed in both patients, and CoExp web tool was used to conduct WGCNA . Results Both patients presented with developmental delay, childhood‐onset ataxia, nystagmus, and seizures. Previously unreported findings were diffuse choreoathetosis and dystonia of the hands (patient 1) and areas of abnormal magnetic resonance imaging signal in the white matter (patient 2). WGCNA showed that FRMD5 belongs to gene networks involved in neurodevelopment and oligodendrocyte function. Conclusions We expanded the phenotype of FRMD5 ‐related disease and shed light on its role in brain function and development. We recommend including FRMD5 in the genetic workup of childhood‐onset ataxia and nystagmus.