Mutational spectrum of congenital long QT syndrome in Turkey; identification of 12 novel mutations across KCNQ1, KCNH2, SCN5A, KCNJ2, CACNA1C, and CALM1. 2022

Ozlem Akgun-Dogan, and Nihat B Ağaoğlu, and Yasemin K Demirkol, and Levent Doğanay, and Yakup Ergül, and Mehmet Karacan
Division of Pediatric Genetics, Umraniye Training and Research Hospital, Istanbul, Turkey.

Long QT syndrome (LQTS) is of great importance as it is the most common cause of sudden cardiac death in childhood. The diagnosis is made by the prolongation of the QTc interval on the electrocardiography. However, clinical heterogeneity and nondiagnostic QTc intervals may cause a delay in the diagnosis. In such cases, genetic tests such as next-generation sequencing (NGS) panel analysis enable a definitive diagnosis. We present the first study that aimed to expand the LQTS's mutational spectrum by NGS panel analysis from Turkey. Fifty-seven unrelated patients with clinically diagnosed LQTS were investigated using an NGS panel that includes six LQTS-related genes. Clinical aspects, outcome, and molecular analysis results were reviewed. Pathogenic (53%)/likely pathogenic (23%)/variant of unknown significance (4%) variants were detected in any of the genes examined in 79% of the patients. Among all detected variants, KCNQ1(71%) was the most common gene, followed by SCN5A (11%), KCNH2 (10%), CALM1 (5%), and CACNA1C (3%). Twelve novel variants were detected. Among the variants in KCNQ1, the c.1097G>A variant was present in 42% of patients. This variant also composed 31% of the variants detected in all of the genes. Our study expands the spectrum of the variations associated with LQTS with twelve novel variants in five genes. And also it draws attention to the frequency of the KCNQ1 c.1097G>A variant and forms the basis for new studies to determine the possible founder effect in the Turkish population. Furthermore, identifying new variants and clinical findings has importance in elaborating the roles of related genes in pathophysiology and determining the variable expression and incomplete penetration rates in this syndrome.

UI MeSH Term Description Entries
D008133 Long QT Syndrome A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME. Electrocardiogram QT Prolonged
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000072237 ERG1 Potassium Channel One of three members of the ether-a-go-go (EAG) POTASSIUM CHANNELS gene family comprising ether-a-go-go (eag), eag-like (elk) and eag-related (erg) subfamilies. Ether-a-go-go-related gene 1 (ERG1) also known as KCNH2, encodes the pore-forming subunit of a rapidly activating-delayed rectifier potassium channel that plays an essential role in the final repolarization of ventricular action potential. Loss-of-function mutations in human hERG1 is associated with life-threatening ARRHYTHMIA. Ether-A-Go-Go-Related Potassium Channel 1,Kv11.1 Protein-Potassium Channel,Potassium Voltage-Gated Channel, Subfamily H, Member 2,Channel, ERG1 Potassium,Channel, Kv11.1 Protein-Potassium,Ether A Go Go Related Potassium Channel 1,Kv11.1 Protein Potassium Channel,Potassium Channel, ERG1,Protein-Potassium Channel, Kv11.1
D014421 Turkey Country in Southeastern Europe and Southwestern Asia bordering the Black Sea, between Bulgaria and Georgia, and bordering the Aegean Sea and the Mediterranean Sea, between Greece and Syria. The capital is Ankara. Turkiye
D051657 KCNQ1 Potassium Channel A voltage-gated potassium channel that is expressed primarily in the HEART. KCNQ1 Protein,KVLQT1 Protein,Kv7.1 Potassium Channel,Voltage-Gated K+ Channel KCNQ1,Potassium Channel, KCNQ1,Potassium Channel, Kv7.1,Voltage Gated K+ Channel KCNQ1
D062554 NAV1.5 Voltage-Gated Sodium Channel A voltage-gated sodium channel subtype that mediates the sodium ion PERMEABILITY of CARDIOMYOCYTES. Defects in the SCN5A gene, which codes for the alpha subunit of this sodium channel, are associated with a variety of CARDIAC DISEASES that result from loss of sodium channel function. Voltage-Gated Sodium Channel Type 5 Subunit alpha,SCN5A Sodium Channel alpha Subunit,Sodium Channel Protein Type 5 Subunit alpha,Sodium Channel, Voltage-Gated, Type V, alpha Subunit,Type 5 Voltage-Gated Sodium Channel,Voltage-Gated Na+ Channel Na(v)1.5a,Voltage-Gated Sodium Channel Type 5,NAV1.5 Voltage Gated Sodium Channel,Type 5 Voltage Gated Sodium Channel,Voltage Gated Sodium Channel Type 5,Voltage Gated Sodium Channel Type 5 Subunit alpha
D020746 Calcium Channels, L-Type Long-lasting voltage-gated CALCIUM CHANNELS found in both excitable and non-excitable tissue. They are responsible for normal myocardial and vascular smooth muscle contractility. Five subunits (alpha-1, alpha-2, beta, gamma, and delta) make up the L-type channel. The alpha-1 subunit is the binding site for calcium-based antagonists. Dihydropyridine-based calcium antagonists are used as markers for these binding sites. Dihydropyridine Receptors,L-Type Calcium Channels,L-Type VDCC alpha-1 Subunit,L-Type Voltage-Dependent Calcium Channel,Long-Lasting Calcium Channel,Long-Lasting Calcium Channels,Receptors, Dihydropyridine,Dihydropyridine Receptor,L-Type Calcium Channel,L-Type VDCC,L-Type VDCC alpha-2 Subunit,L-Type VDCC beta Subunit,L-Type VDCC delta Subunit,L-Type VDCC gamma Subunit,L-Type Voltage-Dependent Calcium Channels,Calcium Channel, L-Type,Calcium Channel, Long-Lasting,Calcium Channels, L Type,Calcium Channels, Long-Lasting,Channel, Long-Lasting Calcium,L Type Calcium Channel,L Type Calcium Channels,L Type VDCC,L Type VDCC alpha 1 Subunit,L Type VDCC alpha 2 Subunit,L Type VDCC beta Subunit,L Type VDCC delta Subunit,L Type VDCC gamma Subunit,L Type Voltage Dependent Calcium Channel,L Type Voltage Dependent Calcium Channels,Long Lasting Calcium Channel,Long Lasting Calcium Channels,Receptor, Dihydropyridine,VDCC, L-Type
D024661 Potassium Channels, Inwardly Rectifying Potassium channels where the flow of K+ ions into the cell is greater than the outward flow. Inward Rectifier Potassium Channels,IRK1 Channel,Inward Rectifier K+ Channel,Inward Rectifier K+ Channels,Inward Rectifier Potassium Channel,Inwardly Rectifying Potassium Channel,Inwardly Rectifying Potassium Channels,K+ Channels, Inwardly Rectifying,Potassium Channel, Inwardly Rectifying,Channel, IRK1

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