Periodic Genetic Reanalysis Identifies a Novel De Novo NOTCH1 Variant: A Case Report

Abstract

Periodic reanalysis of genomic data plays a pivotal role in refining variant interpretation and resolving previously undiagnosed cases, particularly in the context of rare diseases. We report a female patient presenting with global developmental delay, drug-resistant epilepsy, optic atrophy, congenital heart defects, and craniofacial dysmorphism. An initially deprioritized heterozygous NOTCH1 variant (NM_017617.5: c.4787T>C; p.Leu1596Pro), previously associated with isolated cardiac phenotypes, was later reclassified as likely pathogenic following annual reanalysis through our institutional pipeline. Trio-based whole exome sequencing confirmed the variant's de novo origin, and emerging literature published in 2024 expanded the phenotypic spectrum of NOTCH1-related disorders to include neurologic, ocular, musculoskeletal, craniofacial, and integumentary features-closely mirroring the patient's presentation. This diagnostic refinement enabled tailored clinical management and informed genetic counseling. This case underscores the clinical utility of systematic genomic reanalysis in rare disease diagnostics, where evolving knowledge enables reclassification of previously uncertain variants. Moreover, this case adds to the growing body of evidence, broadening the recognized clinical and molecular landscape of NOTCH1-related disorders.