Clinical heterogeneity in a family with pathogenic variant in the KCNQ1 gene: Dilated cardiomyopathy and Long QT Syndrome

Dilated cardiomyopathy (DCM) is mainly associated with pathogenic variants in genes encoding sarcomeric proteins, Z-disk/cytoskeleton proteins, or intercalated disk proteins. In a few cases, mutations in the SCN5A gene are involved (MIM# 601154). KCNQ1 gene (MIM* 607542) encodes a potassium channel and is not a gene classically associated with forms of DCM. Heterozygous pathogenic variants in this gene, at cardiac level, are mainly responsible for Long QT Syndrome type 1 (LQTS1, MIM# 192500), but are also associated with Short QT Syndrome (SQT2, MIM# 609621) and Atrial Fibrillation Family 3 (ATFB3, MIM# 607554).

In this study, we report a family with a heterozygous pathogenic variant NM_000218.3:c.1637C>T;(p.Ser546Leu) in the KCNQ1 gene and a different phenotypic expression in three generations (Figure 1). At the age of 73, the proband presents a diagnosis of dilated cardiomyopathy, with ICD implantation in secondary prevention, diagnosed with Echocardiogram and cardiac MRI (Figure 2). The daughter is clinically healthy, and the daughter's son has Long QT Syndrome diagnosed after birth and detection of the pathogenic variant.

Genomic DNA of the proband was extracted from peripheral blood using EZ1 Advanced XL (Qiagen), according to the manufacturer's instructions. After Qubit 2.0 quantification, Next Generation Sequencing was performed (Ion Torrent S5 and Ion Chef System) analyzying a panel of genes associated with dilated and arrhythmogenic cardiomyopathy designed by Ion Ampliseq Designer (Thermo Fisher Scientific). Results were analyzed with Ion reporter and Integrated Genome Viewer (IGV).

The genetic test did not detect the presence of pathogenic variants in causative genes associated with dilated/arrhythmogenic cardiomyopathy, however it did detect incidentally the heterozygous presence of the familial missense variant in the KCNQ1 gene: NM_000218.3:c.1637C>T;(p.Ser546Leu).

In literature, a case with a loss of function in the KCNQ1 gene and an overlapping phenotype of DCM, ventricular tachycardia and QT interval prolongation has been reported (1). The phenotypic spectrum of KCNQ1 mutations appears to expand beyond the arrhythmia syndromes known to date. Another study also disclosed a KCNQ1 variant in a 5-year-old girl with cardiac arrest, left ventricular non-compaction syndrome, cardiac hypertrophy and myocardial fibrosis (2).

Our work aims to focus more attention on the pathogenic variants in the KCNQ1 gene and the possible association with dilated cardiomyopathy to collect more case studies and study whether some forms of DCM can be associated with pathogenic variants in the KCNQ1 gene.Figure 1

To the left: CMR of the proband, on the post contrast image (short axis view, at basal level) the area of LGE is found with a transmural pattern in the anterior septal segment. CMR, cardiac magnetic resonance; DCM, dilated cardiomyopathy; LGE, late gadolinium enhancement. To the right: in this short axis view, at medial level, the area of LGE is present in the mid-wall layer of the anterior and inferior septal segments. Courtesy of Medical Genetic Unit Policlinico Tor Vergata.