Channelopathies: Ion Channel Genetic Disorders and Clinical Syndromes

Channelopathies are diseases caused by mutations in genes encoding ion channel subunits or regulatory proteins. They disrupt cellular excitability, secretion, and homeostasis.

Major Classes

Channel	Key Genes	Representative Disorders
Voltage-gated Na⁺ (Nav)	SCN1A, SCN5A, SCN4A, SCN9A	Dravet syndrome, GEFS+, LQT3, Brugada, hyperkalemic periodic paralysis, erythromelalgia, small fiber neuropathy
Voltage-gated K⁺ (Kv)	KCNQ1, KCNH2, KCNJ2, KCNE1	LQT1, LQT2, Andersen-Tawil, short QT, familial atrial fibrillation
Voltage-gated Ca²⁺ (Cav)	CACNA1A, CACNA1S, CACNA1C, RYR2	Familial hemiplegic migraine, EA2, hypokalemic periodic paralysis, malignant hyperthermia, Timothy syndrome, CPVT
Cl⁻ (CLCN1, CFTR, CLCNKB)	CLCN1, CFTR, CLCNKB	Myotonia congenita, cystic fibrosis, Bartter syndrome
Ligand-gated (nAChR, GABAₐ, GlyR)	CHRNA4, CHRNB2, GABRG2, GLRA1	ADNFLE, epilepsy, hyperekplexia
Aquaporins (AQP)	AQP2, AQP1	Nephrogenic diabetes insipidus, cerebral edema

Shared Features

• Episodic/paroxysmal symptoms (triggered by stress, temperature, fasting).
• Variable penetrance/expressivity.
• Often respond to specific ion channel modulators (e.g., Na⁺ blockers for Nav disorders).

Diagnosis

• Clinical phenotyping + genetic testing (panel, exome).
• Functional studies (patch clamp) for variants of uncertain significance.

Precision medicine increasingly targets specific channel dysfunction.