A Mild Neurodevelopmental Phenotype Associated with a Novel BRAT1 Variant: Expanding Genotype–Phenotype Correlations

Background: BRAT1-related disorders constitute a continuous neurodevelopmental spectrum ranging from rigidity and multifocal seizure syndrome, lethal neonatal form (RMFSL) to milder phenotypes characterized by cerebellar involvement and variable developmental impairment. Genotype–phenotype correlations remain incompletely defined, particularly for missense variants that may retain residual function. Objectives: To characterize clinical and molecular findings in a patient with a mild BRAT1-related phenotype. Methods: An 18-year-old boy underwent clinical, neuroradiological, neurophysiological, and genetic evaluations. Exome sequencing with in silico filtering on an ataxia gene panel and parental segregation analysis was performed. BRAT1 protein expression was assessed by Western blot analysis in patient-derived fibroblasts. Results: We report an 18-year-old male carrying compound heterozygous BRAT1 variants, including a recurrent truncating variant (c.294dup) and a novel missense variant (c.1784A>T; p.(Glu595Val)). The patient presented with early-onset global developmental delay, cerebellar ataxia, dysarthria, action tremor, and oculomotor abnormalities without epilepsy. Brain MRI showed marked hypoplasia of the inferior cerebellar vermis associated with a mega cisterna magna, without involvement of the cerebellar hemispheres. Follow-up over more than fifteen years showed relatively preserved functional autonomy in late adolescence (SARA 8.5/40; FARS-ADL 11/36). Western blot analysis of patient-derived fibroblasts revealed low but detectable BRAT1 protein levels (approximately 15–20% of mean control expression), indicating reduced but retained BRAT1 protein expression, compatible with, but not proof of, a residual-function effect. Conclusions: These findings are compatible with a contribution of residual BRAT1 protein expression to phenotypic attenuation in this patient and further expand the mild end of the BRAT1-related disease spectrum. Functional assays performed on readily accessible patient material may improve the interpretation of rare variants in neurodevelopmental disorders.