Discovery of a Novel Variant: Unveiling Epilepsy and Newly Associated Dysmorphic Traits in a Turkish Patient.

INTRODUCTION

Cullin-3, encoded by the , is a core component of the ubiquitin E3 ligase complex. Through binding to specific adapters, this scaffold protein mediates the ubiquitination of a number of substrates, targeting their proteasomal degradation. Pathogenic variations of the are thought to cause autism and neurodevelopmental disorders, but so far, few studies have been associated with the phenotype "neurodevelopmental disorder with or without autism or seizures (NEDAUS, #OMIM: 619239)." This study aimed to present the first Turkish patient with a NEDAUS phenotype exhibiting novel clinical and genotypic findings.

CASE PRESENTATION

A 7-year-old patient with seizure, speech delay, decreased eye contact, and autistic behaviors was referred to our clinic. The patient was evaluated through clinical examination, laboratory tests, and imaging studies. Physical examination revealed extremity findings (brachydactyly, tapering fingers). Single whole-exome sequencing analysis was performed for clinical diagnosis. A novel missense variant, c.368T>A (p.Leu123Gln) in , was discovered in the patient. Additionally, computational studies were employed to gain structural and mechanistic insights into the putative damaging impact of the variant. Computational analyses indicated that the p.Leu123Gln substitution may affect the stability and binding behavior of cullin-3. The detected variant was confirmed by the Sanger method and screened in family members by the same method and was found to be de novo.

CONCLUSION

By presenting the first Turkish case of a novel missense variant with a CUL3-related NEDAUS phenotype, this study contributes to the expansion of the genotypic and phenotypic spectrum of the disease.