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 I_Ks 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.

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.

ID	Sex/Age	Deafness	Symptoms	QTc (s)	Genotype
I:1	M/71	No	None	0.420	T322 T322
I:2	F/65	No	Chest discomfort	0.487	T322 M322
II:1	F/42	No	1 syncope (trigger, exercise)	0.430	T322 M322
II:2	M/43	No	Palpitation, dyspnea	0.420 0.410 0.400	T322 M322
II:3	F/39	No	None	0.400	T322 T322
II:4	F/36	No	dyspnea, palpitation	0.455 0.454 0.444	T322 M322
III:1	F/17	Yes	12 syncope (trigger, exercise) Atrial fibrillation	0.520 0.608	M322 M322
III:2	M/8	Yes	3 syncope (trigger, exercise)	0.512 0.627	M322 M322
III:3	M/16	No	None	0.397	T322 T322
III:4	M/9	No	None	0.447	T322 M322

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 substitution of a threonine residue by a methionine residue at codon 322 (T322M) (Figure 3). The homozygous T322M mutation was also identified in the proband's brother (individual III:2, Figure 1). The parents and family members II:4 and I:2 were heterozygous for the mutation.

The detection of mutation T322M was further confirmed by RFLP analysis showing the presence of only the mutant allele (M322) in the proband and her brother (Figure 1, Table 1). RFLP analysis also demonstrated that family members II:1, II:2, I:2, II:4, and III:4 were heterozygous for the mutation (T322 and M322) and that normal individuals I:1, II:3, and III:3 carried the wild type T322 allele. The M322 allele was not identified in 200 normal Chinese Han nationality controls (data not shown).

In this report, we describe a Chinese family in which a heterozygous mutation in KCNQ1, T322M, resulted in RWS whereas the homozygous mutation resulted in JLNS associated with LQTS and deafness. Heterozygous mutations in the KCNQ1 gene have been reported in Chinese patients with RWS, but no KCNQ1 mutation associated with JLN has been reported in the Chinese population [29]. Thus, the T322M is the first KCNQ1 mutation identified for JLN in the Chinese population.

The penetrance of the phenotype in the family members with homozygous T322M was complete. The two homozygous mutation carriers, III:1 and III:2 (Figure 1), had a markedly prolonged QTc of up to 0.608 s and 0.627 s, respectively, and both had experienced multiple syncopal episodes triggered by exercise and sport. These results are consistent with the finding by Schwartz et al. [24] that JLN is a more severe variant of LQTS than RWS. Interestingly, individual III:1 was affected by both LQTS and atrial fibrillation. Previously, in a Chinese family with atrial fibrillation and KCNQ1 mutation S140G, multiple family members had both LQTS and atrial fibrillation [30]. Further studies are needed to determine whether and how the T322M mutation is associated with atrial fibrillation.

The penetrance of the phenotype of QTc prolongation in heterozygous mutation carriers was not complete. Two carriers, II-1 and II-2, had a normal QTc (Table 1, Figure 1). On the other hand, two carriers, I-2 and II:4, were affected with RWS. The other carrier, III-4, had borderline QTc prolongation. The molecular mechanism that is responsible for the intra-familial variability or variable penetrance of the LQTS phenotype in heterozygous carriers is not clear, but environmental factors and modifying genes are likely possibilities.

This study identified a novel mutation, T322M, in the KCNQ1 gene that caused RWS with high intrafamilial variability in the heterozygous carriers and typical JLNS in the homozygous carriers within a Chinese family. To the best of our knowledge, T322M is the first mutation identified for JLNS in the Chinese population.