INVESTIGATION OF MOLECULAR GENETIC CAUSES OF EPILEPTIC ENCEPHALOPATHIES, NEURODEGENERATIVE DISEASES AND COMPLEX NEUROLOGICAL PHENOTYPES IN CHILDREN IN THE TURKESTAN REGION

Abstract

Introduction. Hard-to-diagnose neurological disorders in children, including epileptic encephalopathies (EE), 
neurodegenerative diseases (NDD), and complex neurological phenotypes (CNP), are characterized by high genetic 
heterogeneity and clinical polymorphism. Deep phenotyping combined with exome sequencing can improve diagnostic 
accuracy and the identification of the molecular-genetic causes of these pathologies. 
This study aims to improve diagnostics by conducting deep phenotyping of patients with EE, NDD, and CNP and 
identifying their molecular-genetic causes through exome sequencing among children in the Turkestan region. 
Materials and Methods. A multicenter cross-sectional study was conducted on 79 children with suspected hereditary 
pathology, selected from a cohort of 250 patients with hard-to-diagnose neurological disorders. The diagnostic approach 
included clinical-neurological examination, deep phenotyping (precise and comprehensive analysis of phenotypic 
abnormalities) using HPO and Phenomizer, and exome sequencing to identify single nucleotide variants (SNVs) and copy 
number variations (CNVs). A frequency analysis was performed, calculating descriptive statistics for discrete data (mean 
values – arithmetic mean, relative values – intensive indicator) using IBM SPSS Statistics 29.0.1.0 software. 
Results. Exome sequencing revealed genetic variations in 51.9% of patients: 87.8% SNVs and 12.2% CNVs. 
Pathogenic and likely pathogenic SNVs accounted for 75%. Deep phenotyping enabled the classification of patients into 
groups: EE (15.2%), NDD (49.4%), and CNP (35.4%) and identified common clinical manifestations (seizure syndrome – 
68.3%, minor developmental anomalies – 60.7%, severe motor impairments – 46.2%). Reverse phenotyping confirmed the 
clinical significance of the identified mutations. 
Conclusions. The results highlight the importance of deep phenotyping and exome sequencing in diagnosing hard-to
diagnose neurological disorders. The integration of these methods into clinical practice enhances diagnostic accuracy. It 
contributes to identifying the molecular mechanisms underlying pathologies, particularly in regions with limited access to 
molecular-genetic studies. This study contributes to global genomics by expanding the understanding of the molecular basis 
of rare neurological disorders.