Case Report: Epidermal growth factor receptor germline variant associated with epilepsy and rare, distinctive cerebral MRI abnormalities

Background Somatic pathogenic variants in EGFR have recently been implicated in lesional focal epilepsy, typically in association with low-grade epilepsy-associated tumors. Germline EGFR variants, however, have not previously been linked to epilepsy-related neuroimaging phenotypes. Case presentation We report a large multigenerational family in which multiple individuals presented with epilepsy, progressive cognitive impairment, and striking, bilateral mesiotemporal and thalamic MRI abnormalities. Through deep phenotyping and reanalysis of exome sequencing data a rare, heterozygous, germline EGFR variant [NM_005228.5:c.866C > A p.(Ala289Asp)] was identified and shown to segregate with the neurological phenotype. Conclusion This case report expands the phenotypic spectrum associated with EGFR by demonstrating that a germline variant can underlie epilepsy and characteristic non-neoplastic MRI abnormalities. Our findings underscore the importance of multidisciplinary re-evaluation of variants of uncertain significance (VUS) and segregation analysis in large families.