Incomplete penetrance of a KANSL1 loss of function variant resolved by RNA analysis,  a case report

Background Epilepsy is a prevalent neurological disorder, affecting approximately 1% of the global population. The extensive clinical and genetic variability in epilepsy makes accurate diagnosis a significant challenge. Case presentation In this study, we describe a girl with a clinical presentation of developmental and epileptic encephalopathy (DEE). Using whole genome sequencing (WGS), we identified several candidate variants in the HNRNPU , NIPBL , and KANSL1 genes with partial overlap with the patient clinical presentation. Subsequent analysis revealed that only the variant in the HNRNPU gene arose de novo while the others were inherited from an unaffected parents. However, the previously reported pathogenic loss of function variant in the KANSL1 gene, inherited from a healthy mother, complicated comprehensive family counseling. A thorough investigation using RNA analysis showed that the variant in the KANSL1 gene is located in a duplicated locus, which is not functional, explaining the assumed incomplete penetrance. Conclusions This case illustrates the importance of integrating WGS with additional analyses to accurately diagnose and understand the molecular basis of incomplete penetrance in the KANSL1 gene.