AUTHOR=Xiong Juan , Liu Zhonghua , Chen Shimeng , Kessi Miriam , Chen Baiyu , Duan Haolin , Deng Xiaolu , Yang Lifen , Peng Jing , Yin Fei 

TITLE=Correlation Analyses of Clinical Manifestations and Variant Effects in KCNB1-Related Neurodevelopmental Disorder

JOURNAL=Frontiers in Pediatrics

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2021.755344

DOI=10.3389/fped.2021.755344

ISSN=2296-2360

ABSTRACT=<p><bold>Objective:</bold><italic>Vitro</italic> functional analyses of <italic>KCNB1</italic> variants have been done to disclose possible pathogenic mechanisms in <italic>KCNB1</italic>-related neurodevelopmental disorder. “Complete or partial loss of function (LoF),” “dominant-negative (DN) effect” are applied to describe <italic>KCNB1</italic> variant's molecular phenotypes. The study here aimed to investigate clinical presentations and variant effects associations in the disorder.</p><p><bold>Methods:</bold> We reported 10 Chinese pediatric patients with <italic>KCNB1</italic>-related neurodevelopmental disorder here. Functional experiments on newly reported variants, including electrophysiology and protein expression, were performed <italic>in vitro</italic>. Phenotypic, functional, and genetic data in the cohort and published literature were collected. According to their variants' molecular phenotypes, patients were grouped into complete or partial LoF, and DN effect or non-dominant-negative (non-DN) effect to compare their clinical features.</p><p><bold>Results:</bold> Nine causative <italic>KCNB1</italic> variants in 10 patients were identified in the cohort, including eight novel and one reported. Epilepsy (9/10), global developmental delay (10/10), and behavior issues (7/10) were common clinical features in our patients. Functional analyses of 8 novel variants indicated three partial and five complete LoF variants, five DN and three non-DN effect variants. Patient 1 in our series with truncated variants, whose functional results supported haploinsufficiency, had the best prognosis. Cases in complete LoF group had earlier seizure onset age (64.3 vs. 16.7%, <italic>p</italic> = 0.01) and worse seizure outcomes (18.8 vs. 66.7%, <italic>p</italic> = 0.03), and patients in DN effect subgroup had multiple seizure types compared to those in non-DN effect subgroup (65.5 vs. 30.8%, <italic>p</italic> = 0.039).</p><p><bold>Conclusion:</bold> Patients with <italic>KCNB1</italic> variants in the Asian cohort have similar clinical manifestations to those of other races. Truncated <italic>KCNB1</italic> variants exhibiting with haploinsufficiency molecular phenotype are linked to milder phenotypes. Individuals with complete LoF and DN effect <italic>KCNB1</italic> variants have more severe seizure attacks than the other two subgroups.</p>