GENETIC INSIGHTS INTO А KAZAKHSTANI FAMILY WITH MULTIPLE NEUROLOGICAL CONDITIONS: A CASE REPORT

Abstract

Introduction. Neurological disorders (ND) are diseases that affect both the central nervous system (CNS) and peripheral nervous system (PNS). The aetiology of neurological disorders is highly diverse and may involve genetic, environmental, metabolic, infectious, immune-mediated, and acquired factors.  Epilepsy, cerebral palsy (CP), and autism spectrum disorder (ASD) are clinically and genetically heterogeneous neurological and neurodevelopmental conditions that frequently manifest during childhood. Although these disorders have distinct core clinical features, considerable phenotypic overlap and comorbidity are observed, suggesting they may share underlying genetic and molecular mechanisms.  Methods. Recruitment of the family, interview and clinical data acquisition, as well as blood sample acquisition, took place at the “National Center for Children's Rehabilitation” NJSC. DNA was isolated using commercially available kits. Whole-exome sequencing (WES) was performed using DNA Prep with Exome 2.0 Plus Enrichment Kit on the NovaSeq-6000 platform. All sequencing reads were mapped to the human reference genome assembly GRCh38 (hg38) using the DRAGEN Platform. Variant annotation was performed using VEP release 116.0. Results. We recruited a family with multiple neurological conditions. The parents were a Kazakh male and female with no family history of neurological or neurodevelopmental conditions. Marriage is non-consanguineous. There are three probands in the family diagnosed with autism spectrum disorder (ASD), focal symptomatic epilepsy, and (ASD) and ataxic cerebral palsy (CP), respectively. Bioinformatic analysis revealed pathogenic/likely pathogenic variants in IL10, CDKN2B, GALC, and SLC12A3 genes. In addition, we identified variants of uncertain significance (VUS), loss-of-function (LoF), compound heterozygous, X-linked, and single de novo mutation, in many genes involved in neurological or neurodevelopmental conditions. Conclusion. Overall, our findings demonstrate substantial genetic heterogeneity within a single family presenting with different neurological and neurodevelopmental phenotypes. The results highlight the challenges of interpreting rare and uncertain variants identified by whole-exome sequencing and emphasize the importance of integrating variant classification, inheritance patterns, segregation analysis, clinical phenotype, and available gene–disease evidence. Further functional studies and accumulation of additional clinical cases will be required to determine the contribution of the identified candidate variants to autism spectrum disorder, epilepsy, and other neurological manifestations in this family.