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

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.

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.

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.