Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange‐Nielsen Syndrome and Romano‐Ward Syndrome

Abstract

KCNE1 encodes a regulatory subunit of the KCNQ1 potassium channel‐complex. Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization. Recessive variants in these genes are associated with Jervell and Lange‐Nielson syndrome (JLNS1 and JLNS2), a cardio‐auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death. Some normal‐hearing carriers of heterozygous missense variants of KCNE1 and KCNQ1 have prolonged QT intervals, a dominantly inherited phenotype designated Romano‐Ward syndrome (RWS), which is also associated with arrhythmias and elevated risk of sudden death. Coassembly of certain mutant KCNE1 monomers with wild‐type KCNQ1 subunits results in RWS by a dominant negative mechanism. This paper reviews variants of KCNE1 and their associated phenotypes, including biallelic truncating null variants of KCNE1 that have not been previously reported. We describe three homozygous nonsense mutations of KCNE1 segregating in families ascertained ostensibly for nonsyndromic deafness: c.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). Some individuals carrying missense variants of KCNE1 have RWS. However, heterozygotes for loss‐of‐function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2, indicating a complex genotype‐phenotype spectrum for KCNE1 variants.

Single Cell and Single Nucleus RNA-Seq Reveal Cellular Heterogeneity and Homeostatic Regulatory Networks in Adult Mouse Stria Vascularis

“…We identify a subset of deafness genes that are expressed in adult SV cell types. Deafness genes expressed in marginal cells include Lrp2, Esrrb, Hgf, Kcnq1, Kcne1, Ror1, and Eya4 (Wayne, 2001;Wangemann, 2002;Zhang et al, 2004;Collin et al, 2008;König et al, 2008;Schultz et al, 2009;Khalifa et al, 2015;Faridi et al, 2019). Deafness genes expressed in intermediate cells include Met, Pde1c, and Pax3 (Tassabehji et al, 1993;Bondurand, 2000;Mujtaba et al, 2015;Wang et al, 2018).…”

“…Mutations in genes expressed by marginal, intermediate and basal cells in the SV are known to cause deafness and dysfunction in EP generation. In marginal cells, mutations in Kcnq1, Kcne1 and Barttin (Bsnd) result in a loss or reduction of EP and deafness (Rickheit et al, 2008;Chang et al, 2015;Faridi et al, 2019). Kcnq1/Kcne1 encode the voltage-gated potassium channel Kv7.1 and play a crucial role in secreting potassium and maintaining the EP.…”

The evolution of gene‐guided management of inherited arrhythmia syndromes: Peering beyond monogenic paradigms towards comprehensive genomic risk scores

“…deafness, owing to its also being expressed in the inner ear (analogous to KCNQ1). 31,32 In an effort to better explore the clinical and genetic aspects of LQT5, we conducted an international multicenter collaboration that evaluated 229 individuals, including 89 probands with an LQTS phenotype and 140 family members. 28 Although the degree of QT lighted surprisingly low penetrance levels in many genotype positive family members.…”

Single cell and single nucleus RNA-Seq reveal cellular heterogeneity and homeostatic regulatory networks in adult mouse stria vascularis

“…We identify a subset of deafness genes that are expressed in adult SV cell types. Deafness genes expressed in marginal cells include Lrp2, Esrrb, Hgf, Kcnq1, Kcne1, Ror1, and Eya4 (Collin et al, 2008;Faridi et al, 2019;Khalifa et al, 2015;König et al, 2008;Schultz et al, 2009;Wangemann, 2002;Wayne, 2001;Zhang, Knosp, Maconochie, Friedman, & Smith, 2004). Deafness genes expressed in intermediate cells include Met, Pde1c, and Pax3 (Bondurand, 2000;Mujtaba et al, 2015;Tassabehji et al, 1993;Wang et al, 2018).…”

“…Mutations in genes expressed by marginal, intermediate and basal cells in the SV are known to cause deafness and dysfunction in EP generation. In marginal cells, mutations in Kcnq1, Kcne1 and Barttin (Bsnd) result in a loss or reduction of EP and deafness (Chang et al, 2015;Faridi et al, 2019;Rickheit et al, 2008). Kcnq1/Kcne1 encode the voltage-gated potassium channel Kv7.1 and play a crucial role in secreting potassium and maintaining the EP.…”