Circulation. Genomic and precision medicine · 2025
Functional Profiling of KCNE1 Variants Informs Population Carrier Frequency of Jervell and Lange-Nielsen Syndrome Type 2.
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Vanoye Carlos G, Desai Reshma R, John Jordan D, Hoffman Steven C, Fink Nicolas, Zhang Yue, Venkatesh Omkar G, Roe Jonathan, Adusumilli Sneha, Jairam Nirvani P, Sanders Charles R, Gordon Adam S, George Alfred L
Аннотация
BACKGROUND: Congenital long-QT syndrome is most often associated with pathogenic variants in KCNQ1 encoding the pore-forming voltage-gated potassium channel subunit (KCNQ1) of the slow delayed rectifier current (IKs). Generation of IKs requires assembly of KCNQ1 with an auxiliary subunit (KCNE1) encoded by KCNE1, which is also associated with long-QT syndrome, but the causality of autosomal dominant disease is disputed. By contrast, KCNE1 is an accepted cause of recessive Jervell and Lange-Nielson syndrome type 2 (JLN2). The functional consequences of most KCNE1 variants have not been determined, and the population prevalence of JLN2 is unknown.
METHODS: We determined the functional properties of 95 KCNE1 variants coexpressed with KCNQ1 in heterologous cells using high-throughput voltage-clamp recording. Experiments were conducted with each KCNE1 variant expressed in the homozygous state, and then a subset was studied in the heterozygous state. The carrier frequency of JLN2 was estimated by considering the population prevalence of dysfunctional variants.
RESULTS: There is substantial overlap between disease-associated and population KCNE1 variants. When examined in the homozygous state, 68 KCNE1 variants exhibited significant differences in at least 1 functional property compared with wild-type KCNE1, whereas 27 variants did not significantly affect function. Most dysfunctional variants exhibited loss-of-function properties. We observed no apparent dominant-negative effects when variant and wild-type KCNE1 were coexpressed. Most variants were scored as variants of uncertain significance, and inclusion of functional data resulted in revised classifications for 14 variants. The population carrier frequency of JLN2 was calculated as 1 in 1034. Peak current density and activation voltage-dependence, but not other biophysical properties, were correlated with findings from a mutational scan of KCNE1.
CONCLUSIONS: Among 95 disease-associated or population KCNE1 variants, many exhibit abnormal functional properties without apparent dominant-negative behaviors. Using functional data, we inferred a population carrier frequency for recessive JLN2. This work helps clarify the pathogenicity of KCNE1 variants.
METHODS: We determined the functional properties of 95 KCNE1 variants coexpressed with KCNQ1 in heterologous cells using high-throughput voltage-clamp recording. Experiments were conducted with each KCNE1 variant expressed in the homozygous state, and then a subset was studied in the heterozygous state. The carrier frequency of JLN2 was estimated by considering the population prevalence of dysfunctional variants.
RESULTS: There is substantial overlap between disease-associated and population KCNE1 variants. When examined in the homozygous state, 68 KCNE1 variants exhibited significant differences in at least 1 functional property compared with wild-type KCNE1, whereas 27 variants did not significantly affect function. Most dysfunctional variants exhibited loss-of-function properties. We observed no apparent dominant-negative effects when variant and wild-type KCNE1 were coexpressed. Most variants were scored as variants of uncertain significance, and inclusion of functional data resulted in revised classifications for 14 variants. The population carrier frequency of JLN2 was calculated as 1 in 1034. Peak current density and activation voltage-dependence, but not other biophysical properties, were correlated with findings from a mutational scan of KCNE1.
CONCLUSIONS: Among 95 disease-associated or population KCNE1 variants, many exhibit abnormal functional properties without apparent dominant-negative behaviors. Using functional data, we inferred a population carrier frequency for recessive JLN2. This work helps clarify the pathogenicity of KCNE1 variants.