Authors :
Presenting Author: Malin Zaddach, MD – University Hospital, Ludwig-Maximilians-University Munich
Leonie Grosse, MD – University Hospital, Ludwig-Maximilians-University Munich
Allison Rosenberg, PhD – Cure KCNH1 Foundation
Michaelle Jinnette, Master – Cure KCNH1 Foundation
Matias Wagner, MD – Technical University of Munich, School of Medicine, Institute of Human Genetics,
Ingo Borggraefe, MD – University Hospital, Ludwig-Maximilians-University Munich
Rationale:
Variants in genes encoding potassium channels can lead to neuronal excitation disturbance. KCNH1 encodes Kv10.1, the pore forming subunit of the delayed rectifier potassium channel, thought to restore resting membrane potential. KCNH1 variants are associated with two rare developmental spectrum diseases (Zimmermann-Laband and Temple-Baraitser-syndrome). However, KCNH1 is associated with a much broader clinical spectrum, including for example isolated epilepsy and intellectual disability. Therapeutic approaches under development include antisense oligonucleotides, small molecules and drug repurposing strategies. To date, phenotypic data is limited to retrospective case series. Therefore, reliable data as a basis to define outcomes of intervention studies is missing. This study aims to unravel genotype-phenotype correlation and assess the developmental, seizure and motor phenotypes of individuals with causative variants in KCNH1.
Methods:
A natural history study on KCNH1-related disorders was initiated as a collaborative project with the Cure KCNH1 Foundation. The Cure KCNH1 Foundation opened their patient registry in 2025. Participants are caregivers of affected individuals. They provide longitudinal medical information via questionnaires. At the time point of abstract submission 49 patients were registered from 14 different countries. We also used the software tool prefeKt, a multi-task learning support vector machine model, with published genetic variant data to classify the functional effects of missense variants. Genetic variants were analyzed by region and correlated with available clinical data to identify genotype-phenotype correlations.
Results:
At the time of abstract submission, we included all available 27 published genetic variants in our computational analysis. Of the 27 missense variants, 22 are predicted to be Gain-of-Function (GOF) and 5 to be Loss-of-Function (LOF). 7 are localized in the transmembrane S4 domain, which acts as a voltage sensor. 8 are in the channel pore domain S6. The other variants are in the intramembrane domain H5, domain S3 (acts as a voltage sensor), the cytosolic region and in the cyclic nucleotide-binding homology domain (CNBHD) and post-CNBHD. The 5 LOF variants are localized in domain S6, post-CNBHD, CNBHD and PAS (molecular sensor). Published clinical data showed that seizures were present in 81% of affected individuals. Developmental delay was diagnosed in 89% and hearing loss in 16% of patients. There was no correlation between the clinical picture and predicted LOF or GOF variants thus far.
Conclusions:
This is the first natural history study of KCNH1-related disorders. Variants are mostly computationally predicted to be GOF and cluster in certain hotspots. So far, no statement regarding genotype-phenotype correlation could be made, however patient recruitment and data analysis are ongoing. Genotype-phenotype analysis of the comprehensive dataset will provide novel insights to disease mechanism. Paired with a description of the natural evolution of the disorder, this will provide a useful basis for future studies and clinical trials.
Funding: No funding