Optical genome mapping identifies previously undetected causal variants in early-onset developmental epileptic encephalopathies.

Abstract

Background: Optical genome mapping (OGM) is a novel technology that enables high-resolution detection of structural variants. This study aimed to evaluate the diagnostic contribution of OGM in early-onset developmental epileptic encephalopathies (DEEs) with unresolved genetic causes.

Materials and methods: A total of 38 children with early-onset DEEs (aged 0-18 years) who remained undiagnosed despite conventional karyotyping, chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) were included. All patients underwent detailed phenotypic reassessment and WES reanalysis. One patient received a definitive molecular diagnosis following WES reanalysis. Four patients subsequently withdrew consent, and one patient was excluded due to inadequate DNA quality for OGM. OGM was therefore performed in the remaining 32 patients. Potential OGM findings were validated using appropriate laboratory techniques.

Results: Among the 32 patients who underwent OGM, three candidate structural variants were identified. Two variants (2/32, 6.3%), ogm[GRCh38] ins(X;?)(q27.3;?) and ogm[GRCh38] 6p24.1 (13083829_13279761)x1, were confirmed using orthogonal validation methods, resulting in the molecular diagnoses of Fragile X syndrome and PHACTR1-related DEE, respectively.

Conclusion: OGM contributed to the identification of clinically relevant structural variants in genetically undiagnosed early-onset DEEs. These findings support the complementary role of OGM in the genetic evaluation of complex neurodevelopmental disorders.