Orlando, et al. (2022, PMID: 36361691) analyzed an 8-year-old female patient affected by developmental and epileptic encephalopathy. The patient’s development was unremarkable until 16 months of age, when neurodevelopmental regression was observed, with deteriorating vigilance, feeding challenges, and asthenic body habitus, following the first event of seizures associated with fever. Subsequently, she experienced afebrile generalized tonic-clonic, focal to bilateral tonic-clonic, and myoclonic seizures, accompanied by resistance to anti-seizure medications, which did not cause a major benefit or worsening of epilepsy and development. The authors first assessed the patient when she was 5 years of age. She demonstrated severe cognitive and intellectual disability, reduced human engagement, reduced eye contact, a lack of speech, behavioral impairments, and intermediate axial hypotonia and hyporeflexia. 

A balanced translocation that included the long arm of chromosomes 2 and 18 was discovered by cytogenetic analysis, and chromosomal microarray analysis discovered a small de novo 2q24.3 microdeletion, that encompassed the SCN2A gene. These findings did not appear to be sufficient to explain the fast development and complexities of clinical outcomes. Therefore, optical genome mapping (OGM) and genome sequencing were applied to further characterize the rearrangement. For variant annotation, Geneyx Analysis was used, which combines an exhaustive gene-phenotype interpretation tool with thorough filtering competence within a consolidated user interface that supports browsing, viewing, and interpretation, enabling effective review and variant evaluation by the genetic analyst. 

OGM and genome sequencing revealed a complex genomic rearrangement that included the 2q24.3 region, with four breakpoints, two delimiting the defined SCN2A gene deletion one overlapping the translocation breakpoint, and one into the first intron of the SCN1A gene. The inversion lead to the 5′ UTR region and the first exon of the SCN1A gene to be shifted, resulting in possible gene inactivation. To the best of the authors’ knowledge, this is the first patient to have both the SCN1A and SCN2A genes inactivated at the same time. The loss of function of SCN1A and the simultaneous deletion of SCN2A genes, characterized in part using Geneyx, led to an improved understanding of the patient’s complex phenotype.