![]() This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. Genome Medicine volume 14, Article number: 62 ( 2022) ![]() Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome
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