Expanding the Phenotypic and Functional Evidence for KCNK3 as a Neurodevelopmental Disorder Gene: A New Chinese Case and Drosophila Validation.
Neurodevelopmental disorders (NDDs) are a group of developmental brain disorders caused by various genetic or acquired factors. OMIM has only recently associated the KCNK3 gene with developmental delay associated with sleep apnea (DDSA). Most prior studies on the KCNK3 gene have focused on PAH and cardiovascular diseases. In a 2-year-old girl presenting with generalized hypotonia and delayed language development, we identified a de novo missense variant in KCNK3 through the reanalysis of trio-whole exome sequencing (trio-WES) data. To further explore the relationship between KCNK3 and neurodevelopmental phenotypes, we conducted bidirectional expression regulation of the homologous gene Task7 based on the Drosophila model. Both overexpression and knockdown of the Task7 gene induced anxiety-like behaviors and impaired learning and memory. Notably, Task7 overexpression also led to reduced climbing ability and abnormal sleep patterns; collectively, these four phenotypes recapitulate the characteristic hallmarks of human neurodevelopmental disorders. This study represents the first application of a Drosophila model to demonstrate that KCNK3 functions as a dosage-sensitive regulator of neurodevelopment. While the underlying mechanisms remain to be fully elucidated, these findings position KCNK3 as a candidate gene for molecular screening and pave the way for future functional studies and therapeutic exploration in NDDs.