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

Area of Science:

• Genomics
• Rare Diseases
• Clinical Genetics

Background:

• Periodic reanalysis of genomic data is vital for refining variant interpretation and diagnosing rare diseases.
• A patient presented with global developmental delay, epilepsy, optic atrophy, heart defects, and craniofacial dysmorphism.

Purpose of the Study:

• To report the diagnostic utility of systematic genomic reanalysis in a patient with a complex phenotype.
• To highlight the expanding clinical and molecular spectrum of NOTCH1-related disorders.

Main Methods:

• Trio-based whole exome sequencing was performed.
• Genomic data was reanalyzed periodically using an institutional pipeline.
• Literature review was conducted on NOTCH1-related disorders.

Main Results:

• An initially uncertain heterozygous NOTCH1 variant (c.4787T>C; p.Leu1596Pro) was reclassified as likely pathogenic.
• The variant was confirmed to be de novo.
• The patient's phenotype closely matched the expanded spectrum of NOTCH1-related disorders, including neurologic and craniofacial features.

Conclusions:

• Systematic genomic reanalysis is clinically valuable for rare disease diagnosis, enabling variant reclassification as knowledge evolves.
• This case broadens the recognized clinical and molecular landscape of NOTCH1-related disorders.