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

INTRODUCTION

The clinical presentation of most early-onset neu- rological disorders is ambiguous due to their heteroge- neous manifestation and symptom non-specificity (1). In recent years, genetic testing has become a useful diag- nostic tool for identifying genetic mutations associated with rare neurological disorders. However, even Whole Exome Sequencing (WES) – a technique which allows for analysis of all exons in a patient’s genome – often results in the identification of multiple genetic variants which may potentially explain a patient’s complex clini- cal picture. In such cases, segregation analysis becomes an indispensable method for clarifying the significance of the variants. The diagnostic process is further compli- cated if one of the parents is not available for segregation analysis, which is the case in In Vitro Fertilization (IVF) with donor material. In the following case study, we present a patient with a complex neurological syndrome with accompanying facial abnormalities, who was conceived through IVF with donor sperm. Via analysis of the WES data one hetero- zygous genetic variant in the EPHA4 gene was selected as a target. The Ephrin Receptor A4 (EPHA4) gene, located on the long arm of human chromosome 2 (2q36.1), is a pro- tein encoding gene producing a Protein Tyrosine Kinase (PTK) receptor. Although within the Central Nervous Sys- tem (CNS) EPHA4 has been implicated in processes such as neural migration, axonal proliferation, and synaptic plasticity (2), its pathogenicity in clinical practice is not well understood. In humans, thus far, only one germline likely pathogenic missense point mutation has been re- ported in a male patient with atypical cerebral palsy (3) and Van Hoecke et al. (4) showed that decreased EPHA4 expression was significantly correlated with later onset of Amyotrophic Lateral Sclerosis (ALS). Light et al. (2) have reported several somatic genetic variants in relation to melanoma tumors. On the other hand, studies with animal models, ranging from rodents to primates, have shown that EphA4 expression plays a role in various severe CNS dis- orders. Fu et al. (5) showed that blocking EphA4 activity in mice had a positive effect on the hippocampal plasticity, typically ravaged by Alzheimer’s disease. Goldshmit and Bourne (6) found that astrocytic upregulation of EphA4 in non-human primates has an indirect inhibitory effect on axonal regrowth and regeneration following a Traumatic Brain Injury (TBI).

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