Balkan Journal of Medical Genetics

EPHA4 GENETIC VARIANT IN A PATIENT WITH EPILEPSY, OPHTHALMOLOGICAL ANOMALIES, AND NEURODEVELOPMENTAL DELAY
Sleptsova M, Georgiev C, Atemin S, Dimova P, Avdjieva-Tzavella D, Tacheva G, Litvinenko I, Grozdanova L, Todorov T, Mitev V, Todorova A
*Corresponding Author: Mila Sleptsova, BSc, Genetic Medico-Diagnostic Laboratory “Genica”, 84 Ami Bue Street, Sofia, Bulgaria; Email: milasleptsova99@gmail.com
page: 65

DISCUSSION

Mutations in the EPHA4 gene are compatible with optic nerve defects and severe abnormalities in the cen- tral nerve system. The reasons behind our focus on the genetic variant c.1655_1656del, p.(Ser552CysfsTer23) in the EPHA4 gene are described below. MetaDome (9) indicates that the identified EPHA4 genetic variant is located in the beginning of the protein’s transmembrane domain (IPR027936; Figure 1). This type of domain is characteristic for ephrin receptors and is re- sponsible for the oligomerization of these receptors and for successful signaling (IPR027936) (10). Due to this localization, the frameshift variant could affect the pro- tein’s ability to integrate into the cell membrane and func- tion as an ephrin receptor in the CNS. To the best of our knowledge, this is the first identification of a frameshift genetic variant in the transmembrane domain of the EphA4 protein. The only reported likely pathogenic variant in ClinVar (3) falls within the kinase region of the protein. Moreover, the genetic variant is not found in the gnomAD v2.1.1 controls and EPHA4’s pLI score is 1, which indicates that the gene is highly intolerant to loss of function variants (11,12). As the genetic variant does not abide the 50-55 nt boundary rule (13), we can assume that the produced mRNA undergoes nonsense-mediated decay. It has been suggested previously that mutations in ephrin receptor genes, causative of nonsense-mediated decay, lead to pathogenesis (14). Recently, a number of EPHA4-cases emerged in the GeneMatcher platform (15), helping understand the patho- physiology of severe neurological cases having EPHA4 gene variants in common. Based on this new understand- ing, the variation in EPHA4 seems highly compatible with our patient’s clinical manifestation. Unfortunately, we cannot confirm that the genetic variant has occurred de novo, due to the lack of a paternal sample. Furthermore, Oliver et al. (16) have published a comprehensive list of epilepsy-related genes, wherein EPHA4 is not included. With this study we bring attention to the EPHA4 gene as a potential target for additional functional studies in as- sociation with neurodevelopmental disorders, including epilepsy. Moreover, we emphasize on the difficulties in classifying genetic variants when DNA from donors is not available for genetic testing.

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