Genetic variants for long QT syndrome among infants and children from a statewide newborn hearing screening program cohort

Abstract

Objectives: Autosomal recessive long QT syndrome (LQTS), or Jervell and Lange-Nielsen syndrome (JLNS), can be associated with sensorineural hearing loss. We aimed to explore newborn hearing screening combined with electrocardiograms (ECGs) for early JLNS detection.

Study design: In California, we conducted statewide, prospective ECG screening of children ≤ 6 years of age with unilateral or bilateral, severe or profound, sensorineural or mixed hearing loss. Families were identified through newborn hearing screening and interviewed about medical and family histories. Twelve-lead ECGs were obtained. Those with positive histories or heart rate corrected QT (QTc) intervals ≥ 450 ms had repeat ECGs. DNA sequencing of 12 LQTS genes was performed for repeat QTc intervals ≥ 450 ms.

Results: We screened 707 subjects by ECGs (number screened/number of responses = 91%; number of responses/number of families who were mailed invitations = 54%). Of these, 73 had repeat ECGs, and 19 underwent gene testing. No subject had homozygous or compound heterozygous LQTS mutations, as in JLNS. However, 3 individuals (with QTc intervals of 472, 457, and 456 ms, respectively) were heterozygous for variants that cause truncation or missplicing: 2 in KCNQ1 (c.1343dupC or p.Glu449Argfs*14; c.1590+1G>A or p.Glu530sp) and 1 in SCN5A (c.5872C>T or p.Arg1958*).

Conclusions: In contrast to reports of JLNS in up to 4% of children with sensorineural hearing loss, we found no examples of JLNS. Because the 3 variants identified were unrelated to hearing, they likely represent the prevalence of potential LQTS mutations in the general population. Further studies are needed to define consequences of such mutations and assess the overall prevalence.

Figure 1

Summary of subject recruitment, cardiac screening, and risk assessment. Numbers of subjects are in parentheses.

Figure 2

ECG results in the newborn hearing screening study. A. Distribution of QTc intervals among 707 participants. Shaded bars indicate QTc intervals ≥450 ms. B. ECG of the 25-month-old girl with the KCNQ1 p.Glu449Argfs*14 variant. C. ECG of the 4-month-old girl with the KCNQ1 p.Gln530sp variant. D. ECG of the 47-month-old boy with the SCN5A p.Arg1958* variant.

Figure 3

Sites of the KCNQ1 and SCN5A variants found in the newborn hearing screening and ECG study. A. Sites of the KCNQ1 p.Glu449Argfs*14 (shown by *449) and p.Gln530sp (shown by *530) mutations in the C-terminus (amino acids 352-676). KCNQ1 forms a tetrameric channel. Each KCNQ1 monomer is shown as 2 spheres of the same color (striped spheres represent pore forming domains; plain spheres represent voltage sensor domains). The cytoplasmic C-terminus with its 4 helices (A-D) is shown for 2 KCNQ1 monomers. The p.Glu449Argfs*14 mutation disrupts the C-terminus after position 448, removing helices B, C, and D. The p.Gln530sp mutation disrupts the C-terminus after position 530 (in helix B). B. Site of the SCN5A p.Arg1958* variant (shown by *1958) in the C-terminus (amino acids 1785-2016). SCN5A (a) forms a complex with sodium channel β subunits (b), neuronal nitric oxide synthase 1 (c), plasma membrane Ca⁺⁺ transporting ATPase 4 (d), α1-syntrophin (e), the dystroglycan complex (f), and cytoskeletal scaffolding. The scaffold contains dystrophin (g), dystrobrevin (h), laminins (i), F-actin (j), syncoilin (k), and desmin (l). Loss of the C-terminal residues in the p.Arg1958* variant is predicted to untether SCN5A from the macromolecular complex.