Identification of a novel KCNQ1 mutation associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long QT syndrome in a Chinese family

Su Zhang 1 2 Ke Yin 2 Xiang Ren 2 Pengyun Wang 2 Shirong Zhang 2 Lingling Cheng 1 2 Junguo Yang 0 2 Jing Yu Liu 2 Mugen Liu 2 Qing Kenneth Wang 2 3 0 Department of Cardiology, Union Hospital, Huazhong University of Science and Technology , Wuhan , P. R. China 1 Hubei Vocational Technical College , Xiaogan, Hubei , P. R. China 2 Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology , Wuhan , P. R. China 3 Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University , Cleveland, Ohio , USA Background: Long QT syndrome (LQTS) is a cardiac disorder characterized by prolonged QT intervals on electrocardiograms (ECG), ventricular arrhythmias, and sudden death. Clinically, two inherited forms of LQTS have been defined: autosomal dominant LQTS or Romano-Ward syndrome (RWS) not associated with deafness and autosomal recessive LQTS or Jervell and Lange-Nielsen syndrome (JLNS) associated with deafness. Methods: A Chinese family with both RWS and JLNS was identified. Family members were diagnosed based on the presence of a prolonged QT interval as seen on a 12-lead ECG and a medical history of syncope, palpitation, and deafness. Mutational studies in the KCNQ1 potassium channel gene were performed using direct DNA sequence analysis and restriction length polymorphism analysis. Results: The proband in the Chinese family and her brother had previously been diagnosed with JLNS, and two other members were affected with RWS. The proband was also affected with atrial fibrillation. A single nucleotide substitution of C to T at nucleotide 965 of KCNQ1 was identified, and the mutation resulted in the substitution of a threonine residue at codon 322 by a methionine residue (T322M). The novel heterozygous T322M mutation was identified in two patients with RWS, one member with borderline QTc, and two normal family members. The two JLNS patients in the family carried the homozygous T322M mutation. The T322M mutation was not found in 200 Chinese normal controls. Conclusion: Our results suggest that T322M is a novel mutation that caused RWS with high intrafamilial variability in the heterozygous carriers and typical JLNS in the homozygous carriers within this Chinese family. The T322M mutation is the first mutation identified for JLNS in the Chinese population. - Background Long QT syndrome (LQTS) is a disorder of cardiac repolarization characterized by prolonged QT intervals and abnormal T waves on surface electrocardiograms (ECG), torsade de pointes, and sudden death [1-3]. Two forms of inherited LQTS have been described: Romano-Ward syndrome (RWS), which is an autosomal dominant form of LQTS without sensorineural deafness, and Jervell and Lange-Nielsen syndrome (JLNS), which is an autosomal recessive form of LQTS associated with deafness [4-6]. RWS is the most common form of inherited LQTS [7]. More than nine genes have been identified for RWS:KCNQ1 (or KvLQT1, LQT1) [8] on chromosome 11p15.5, KCNH2 (or HERG, LQT2) on chromosome 7q35-36 [9], SCN5A (LQT3) on chromosome 3p21 [10,11], Ankyrin-B (LQT4) on chromosome 4q25-27 [12], KCNE1 (LQT5) on chromosome 21q22 [13,14], KCNE2 (LQT6) on chromosome 21q22 [15], KCNJ2 (LQT7) 17q23.1 [16], CACNA1C (LQT8) on chromosome 12p13.3 [17], and CAV3 (LQT9) on chromosome 3p25 [18]. Carriers with mutations in KCNJ2 and CACNA1C exhibit not only the LQTS phenotype but other phenotypes as well (designated as Andersen syndrome and Timothy syndrome, respectively) [16,17]. JLNS is a rare autosomal recessive disorder that appears to have a worse prognosis than RWS [19]. JLNS can be caused by homozygous or compound heterozygous mutations in either KCNQ1 or KCNE1 [13,20-27]. KCNQ1 encodes a potassium channel gene with six transmembrane domains and forms functional IKs potassium channels by assembling with minK (encoded by KCNE1) in the heart [8,28]. In this report, we identified a novel mutation in the KCNQ1 gene that simultaneously caused RWS and JLNS within a Chinese family. The results expand the spectrum of KCNQ1 mutations causing RWS and JLNS. Results One three-generation JLN/RWS family was identified in China and clinically evaluated. The pedigree structure of the family is shown in Figure 1, and clinical characteristics for family members are listed in Table 1. The proband (patient III:1) had been deaf since birth. At 3 years of age, she was referred for detailed examinations due to syncope. Since then, she has experienced 11 additional syncopal episodes, most of which were preceded by exercise and sport. Current ECG analysis revealed a markedly prolonged QTc ranging from 0.520 to 0.608 s (a representative ECG is shown in Figure 2). She was then diagnosed as having JLNS (deafness + LQTS). Interestingly, the proband was also affected with atrial fibrillation. The proband's brother (patient III:2, Figure 1) was also affected with deafness and LQTS (JLNS). His QTc ranged from 0.512 s to 0.627 s, and he had experienced three syncopal episodes in the past triggered by exercise and sport. Their parents had normal hearing and normal ECGs with a QTc of 0.42 s (father) and 0.43 s (mother). Individual II:1 had experienced one syncopal episode triggered by exercise when she was 20 years old. No syncope was identified for individual II:2, but he had experienced palpitation and dyspnea. The parents' marriage was not consanguineous. Further analysis of other family members identified two other members affected with RWS. Individual II:4 was clinically diagnosed with LQTS because she had a moderately prolonged QTc of 0.455 s and a medical history of dyspnea and palpitation. Her mother (I:2, Figure 1) was also affected with LQTS with a prolonged QTc of 0.487 s. Both I:2 and II:4 had normal hearing. Individual III:4 was a male with a borderline QTc of 0.447 s. No stress testing was performed for III:4 or other family members. Individuals I:1, II:3, and III:3 had a normal QTc of 0.420 s, 0.400 s, and 0.397 s, respectively. A homozygous C T transition was identified at nucleotide 965 in exon 7 of KCNQ1 in the DNA sample from the proband (Figure 3). The C to T change resulted in the PFeigduigrree1structure of the Chinese family with JLNS and RWS Pedigree structure of the Chinese family with JLNS and RWS. The results of RFLP analysis for mutation T322M are shown below each symbol. Affected male III:1 and females I:2 and III:2 are indicated with filled squares and circles; normal members are indicated with open symbols; individual III:4 with borderline QTc is shown with a gray symbol. QTc for family members is shown below each symbol as ms. The three-generation family is notable for the proband (III:1, indicated by an arrow) and her brother (III:2), who were affected with (...truncated)