TNNI3 and KCNQ1 co-inherited variants in a family with hypertrophic cardiomyopathy and long QT phenotypes: A case report

Abstract

QTc prolongation is reported in patients with hypertrophic cardiomyopathy (HCM). However, the causes of the QTc interval increase remain unclear. The main contribution to QTc prolongation in HCM is attributed to the myocardial hypertrophy and related structural damage. In a 24-year-old male proband, affected by HCM and long QTc, we identified by Next Generation Sequencing a pathogenic variant in gene TNNI3 co-inherited with a damaging variant in KCNQ1 gene. This evidence suggests the possibility that QTc interval prolongation and its dispersion in HCM could be associated not only to the severity of left ventricular hypertrophy but also to the co-inheritance of pathogenic variants related to both long QT Syndrome (LQTS) and HCM. Although the simultaneous presence of pathogenic variants in genes related to different heart diseases is extremely rare, counseling and genetic testing appear crucial for the clinical diagnosis. Screening of LQTS genes should be considered in HCM patients to clarify the origin of long QTc, to provide more information about the clinical presentation and to evaluate the incidence of the co-existence of LQTS/HCM gene variants that could occur more frequently than so far reported.

Dual myosin binding protein C3 and potassium voltage-gated channel subfamily H member 2 co-inherited pathogenic variants in a patient with hypertrophic cardiomyopathy and long QT 2 syndrome: A case report

“…Specifically, to our knowledge, only concomitant (likely) pathogenic variants KCNQ1 gene (responsible for congenital LQT1) have been reported in the context of genotype positive HCM. 1,2 This is the first reported case of HCM and concomitant congenital LQT2.…”

“… 1 QT prolongation in HCM has been attributed mostly to dispersion of repolarization from myocardial hypertrophy. 2 We report a rare case of a 25-year-old man with familial HCM and prolonged QT interval, who presented with polymorphic ventricular tachycardia / ventricular fibrillation cardiac arrest. Genetic testing identified a pathogenic heterozygous variant in MYBPC3 (myosin binding protein 3) responsible for HCM, as well as a heterozygous pathogenic variant in KCNH2 (potassium voltage-gated channel subfamily H member 2), associated with long QT syndrome (LQTS) type 2.…”

New Genetic finding in a Combination of Long QT Syndrome and Hypertrophic Cardiomyopathy in a Single Patient

“…Another association between hypertrophic cardiomyopathy and long QT syndrome was reported in the TNNI3 gene, coinherited with a damaging variant in KCNQ1, again with signs of ECG ventricular hypertrophy [10].…”

Long QTc in hypertrophic cardiomyopathy: A consequence of structural myocardial damage or a distinct genetic disease?

“…More recently, the existence of a Chinese family carrying pathogenic variants related to both HCM and LQTS phenotypes has been reported ( 14 ). Moreover, our group recently described a single case of a 24-year-old male, affected by HCM and long QTc, carrying pathogenic variants in both TNNI3 and KCNQ1 genes ( 15 ). Another case-report underscored the association of a de novo CALM2 mutation with LQTS and HCM ( 16 ).…”