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Updated: Jul 7, 2025
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Improved classification and pathogenicity assessment by comprehensive functional studies in a large data set of KCNQ2
Yuwei Zhang1, Yuqing Xue1, Yu Ma2
1Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai 200438, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200438, China; Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen 518132, China.
Aims:
The paucity of functional annotations on hundreds of KCNQ2 variants impedes the diagnosis and treatment of KCNQ2-related disorders. The aims of this work were to determine the functional properties of 331 clinical KCNQ2 variants, interpreted the pathogenicity of 331 variants using functional data，and explored the association between homomeric channel functions and phenotypes.
Main Methods:
We collected 145 KCNQ2 variants from 232 epilepsy patients and 186 KCNQ2 missense variants from the ClinVar database. Whole-cell patch-clamp recording was used to classify the function of 331 variants. Subsequently, we proposed 24 criteria for the pathogenicity interpretation of KCNQ2 variants and used them to assess pathogenicity of 331 variants. Finally, we analyzed the clinical phenotypes of patients carrying these variants, and explored the correlations between functional mechanisms and phenotypes.
Key Findings:
In the homozygous state, 287 were classified as loss-of-function and 14 as gain-of-function. In the more clinically relative heterozygous state, 200 variants exhibited functional impairment, 121 of which showed dominant-negative effects on wild-type KCNQ2 subunits. After introducing functional data as strong-level evidence to interpret pathogenicity, over half of variants (169/331) were reclassified and 254 were classified as pathogenic/likely pathogenic. Moreover, dominant-negative effect and haploinsufficiency were identified as primary mechanisms in DEE/ID and SeLNE, respectively. The degree of impairment of channel function correlated with the phenotype severity.
Significance:
Our study reveals the possible cause of KCNQ2-related disorders at the molecular level, provides compelling evidence for clinical classification of KCNQ2 variants, and expands the knowledge of correlations between functional mechanisms and phenotypes.
