WHOLE-EXOME SEQUENCING OF MONOZYGOTIC TWINS WITH EPILEPSY AND AUTISM SPECTRUM DISORDER IN A KAZAKHSTANI FAMILY: A CASE REPORT

Abstract

Epilepsy and autism spectrum disorder (ASD) frequently co-occur and share complex genetic determinants. However, molecular diagnosis remains challenging because of incomplete penetrance, variable expressivity, and the limited representation of Central Asian populations in genomic reference databases. This case report describes a Kazakhstani family with 9-year-old monozygotic twin girls who developed focal seizures with secondary generalization at approximately one year of age and were subsequently diagnosed with ASD. Family-based whole-exome sequencing was performed for both affected twins and their clinically unaffected, non-consanguineous parents. No pathogenic or likely pathogenic variant explaining the shared epilepsy–ASD phenotype was identified. A paternally inherited NPRL3 missense variant, c.121A>G (p.Lys41Glu), was considered biologically plausible because of the established association of NPRL3 with focal epilepsy. However, it remained a variant of uncertain significance (VUS), was not reported in the queried gnomAD dataset, and had an AlphaMissense score of 0.14. Additional heterozygous VUS were identified in SPTBN4, ANK2, VPS33A, SLC25A46, and GFM1. Two ZC2HC1C variants inherited from different parents supported a possible biallelic hypothesis, but their clinical significance was uncertain. We interpreted a heterozygous pathogenic ALDOB variant as an incidental carrier finding unrelated to the presenting phenotype. This case illustrates the distinction between candidate variants and a molecular diagnosis. Further evaluation may include periodic exome reanalysis, copy-number analysis, genome sequencing, and targeted validation where justified. Broader population reference resources could improve variant interpretation in Kazakhstan.