Jervell and Lange-Nielsen Syndrome due to a Novel Compound Heterozygous KCNQ1 Mutation in a Chinese Family

Abstract

Jervell and Lange-Nielsen syndrome (JLNS) is a rare but severe autosomal recessive disease characterized by profound congenital deafness and a prolonged QTc interval (greater than 500 milliseconds) in the ECG waveforms. The prevalence of JLNS is about 1/1000000 to 1/200000 around the world. However, exceed 25% of JLNS patients suffered sudden cardiac death with kinds of triggers containing anesthesia. Approximately 90% of JLNS cases are caused by KCNQ1 gene mutations. Here, using next-generation sequencing (NGS), we identified a compound heterozygosity for two mutations c.1741A>T (novel) and c.477+5G>A (known) in KCNQ1 gene as the possible pathogenic cause of JLNS, which suggested a high risk of cardiac events in a deaf child. The hearing of this patient improved significantly with the help of cochlear implantation (CI). But life-threatening arrhythmias occurred with a trigger of anesthesia after the end of the CI surgery. Our findings extend the KCNQ1 gene mutation spectrum and contribute to the management of deaf children diagnosed with JLNS for otolaryngologists (especially cochlear implant teams).

Figure 1

Pedigree of Family 1 associated with JLNS. A novel compound heterozygous mutation, c.1741A>T/c.477+5G>A was found in Family member 1-II-1. Family member 1-I-1 and Family member 1-I-2 were heterozygous carriers. The proband is shown in black and indicated by a black arrow. WT: wild type.

Figure 2

CPA results for proband 1-II-1 before and after wearing hearing aids (HAs) and with cochlear implant (CI). (a) Testing results before wearing hearing aids. (b) Testing results after fitting of hearing aids. (c) Sound field thresholds of the right ear 3 months after CI surgery. Arrows: no response at the specific frequency. Cross and circle: threshold at the specific frequency.

Figure 3

ECG detected in Proband 1-II-1. (a) The ECG waveforms before cochlear implantation (CI). Two-way arrow: QT/QTc interval. One-way arrow: dome and dart T wave. (b) The ECG waveforms after cochlear implantation (CI). Two-way arrow: QT/QTc interval. One-way arrows and arrowheads indicate T wave alternans (TWA).

Figure 4

Mutated KCNQ1 sequences of the identified c.1741A>T (above) and c.477+5G>A (below) variant. The mutated nucleotide is shown in red. Red “stop” indicates termination of synthesis. I: boundary of corresponding exon and intron. Red arrows and black rounds: sites of nucleotide changes.

Figure 5

Molecular basis for the case of JLNS is detailed at gene and protein levels and evolutionary conservation of amino acids in A-domain affected by the nonsense mutation. (a) Schematic diagram of 16 exons and 15 introns encoded by biallelic KCNQ1 genes (KCNQ1; NM 000218.3). Two variants were indicated by arrows. Novel mutation is shown in red and known mutation is shown in black. Rectangle: exon. Line: intron. (b) Schematic diagram of α-subunit of IKS encoded by biallelic KCNQ1 genes (KCNQ1; NM_000218.3) with pathogenic mutations of p.K581X (red cross) or IVS2+5G>A (blue rectangle). Six transmembrane segments (S1-S6) are indicated by gray columns and the pore-loop is located between S5 and S6. Green oval: A-domain. Red arrow: novel mutation. Black arrow: previously-reported mutation. (c) Evolutionary conservation of A-domain (head, linker, and tail). Mutated site is indicated by asterisk. Gray residues cannot be translated. Different residues were indicated in blue.