Diagnostic Pitfall in Genomic Era: Discordant SMARCA2 Finding in Patient with Megalencephalic Leukoencephalopathy...

Next-generation sequencing has transformed the diagnostic approach to rare neurogenetic disorders. However, interpretation of molecular findings remains challenging when identified variants are discordant with the clinical phenotype. We report the case of a preschool-aged girl presenting with seizures, infantile-onset macrocephaly, and the characteristic magnetic resonance imaging (MRI) pattern of megalencephalic leukoencephalopathy with subcortical cysts (MLC). Whole-exome sequencing identified no pathogenic variants in the currently recognized MLC-associated genes. Instead, it detected a heterozygous SMARCA2 splice-site variant that was classified as "likely pathogenic" by the testing laboratory according to the American College of Medical Genetics and Genomics criteria. However, the patient's overall clinical presentation was not consistent with the currently recognized spectrum of SMARCA2-related disorders. Comprehensive genotype-phenotype correlation together with a two-year follow-up ultimately supported a diagnosis of classic MLC despite the discordant SMARCA2 finding. This case highlights that molecular findings should complement, rather than override, established clinicoradiological evidence, particularly in disorders with highly characteristic imaging phenotypes.