A novel KCNQ1 nonsense variant in the isoform-specific first exon causes both jervell and Lange-Nielsen syndrome 1 and long QT syndrome 1: a case report

Abstract

Background: According to previous KCNQ1 (potassium channel, voltage gated, KQT-like subfamily, member 1) gene screening studies, missense variants, but not nonsense or frame-shift variants, cause the majority of long QT syndrome (LQTS; Romano-Ward syndrome [RWS]) 1 cases. Several missense variants are reported to cause RWS by a dominant-negative mechanism, and some KCNQ1 variants can cause both Jervell and Lange-Nielsen Syndrome (JLNS; in an autosomal recessive manner) and LQTS1 (in an autosomal dominant manner), while other KCNQ1 variants cause only JLNS. The human KCNQ1 gene is known to have two transcript isoforms (kidney isoform and pancreas isoform), and both isoforms can form a functional cardiac potassium channel.

Case presentation: Here, we report a novel nonsense KCNQ1 variant causing not only JLNS, but also significant QTc prolongation identical to RWS in an autosomal dominant manner. Our case study supports that haploinsufficiency in the KCNQ1 gene is causative of significant QTc prolongation identical to RWS. Interestingly, the nonsense variant (NM_000218.2:c.115G > T [p.Glu39X]) locates in exon 1a of KCNQ1, which is a kidney-isoform specific exon. The variant is located closer to the N-terminus than previously identified nonsense or frame-shift variants.

Conclusion: To the best of our knowledge, this is the first report showing that a nonsense variant in exon 1a of KCNQ1, which is the kidney-isoform specific exon, causes JLNS. Our findings may be informative to the genetic pathogenesis of RWS and JLNS caused by KCNQ1 variants.

Keywords: Case report; Haploinsufficiency; Jervell and Lange-Nielsen Syndrome (JLNS); KCNQ1 (potassium channel Voltage gated, KQT-like subfamily, member 1); Long QT syndrome (LQTS); Phenotype variety; Romano-Ward syndrome (RWS).

Fig. 1

Exon–intron structure and alternative transcripts of the human KCNQ1 gene. The two wild-type isoform transcripts, the kidney and pancreas isoforms, are composed of exons 1a and 1–15 (kidney isoform) encoding 676 amino acids or exons 1b and 1–15 (pancreas isoform) encoding 549 amino acids [1, 4]. The arrow and star indicate the nonsense variant (NM_000218.2:c.115G > T, p.Glu39X) in exon 1a of the KCNQ1 gene. *, both isoforms can form a functional cardiac potassium channel [1, 2]

Fig. 2

Pedigree of the family. The proband is indicated by a black filled circle and an arrowhead. Squares denote males, and circles denote females. Hatched squares or circles denote significant QTc prolongation. QTc intervals are provided for each individual. *, QTc was measured under beta-blocker treatment (metoprolol). **, QTc was measured under treatment with beta-blockers (atenolol and bisoprolol) and other medication (mexiletine). E39X and P448R, nonsense variant (NM_000218.2:c.115G > T) or common variant (NM_000218.2:c.1343C > G) in the KCNQ1 gene. mo., months old; yo., years old; hetero, heterozygous; homo, homozygous; ms, millisecond; N.D., not determined

Fig. 3

Baseline electrocardiogram (ECG) of the proband (II-2), her son (III-1), and her daughter (III-2). Baseline ECG from the proband at 44 years of age a, baseline ECG from the son at 8 months of age b, and baseline ECG from the daughter at 5.25 years old c. Baseline ECG from the proband a was recorded under beta-blockers (atenolol and bisoprolol) and other medication (mexiletine). Baseline ECGs from the children b, c were recorded under beta-blocker treatment (metoprolol)