Rare diseases unlocked: from ‘uncertain’ variants to targeted cures via APC
Ion channels control the flow of ions across membranes, controlling excitability in nerves, muscles, and tissues throughout the body. When ion channel genes are disrupted by rare mutations, the resulting 'channelopathies' manifest as a wide spectrum of rare diseases, from severe developmental epilepsies to inherited cardiac arrhythmia syndromes and episodic muscle disorders. Automated patch clamp is accelerating variant characterization, revealing altered channel function and advancing early drug discovery for rare channelopathies.
Why channelopathies matter in rare disease
Channelopathies are often monogenic, with single missense or truncating variants producing significant effects on channel function and high clinical penetrance in certain families (Kass, 2005). Because many pathogenic mechanisms are mutation-specific (loss- versus gain-of-function, trafficking defects, altered kinetics), a detailed biophysical read-out is essential to direct therapy.
Automated patch clamp as a tool to bridge genetics to rare disease therapies
Manual patch clamp has long been seen as the fundamental technique in ion channel current recordings, but it is technically challenging, slow, and highly labor-intensive. Automated patch clamp (APC) platforms scale electrophysiology to hundreds or thousands of variants and/or compounds, enabling systematic and reproducible measurement of gating, conductance, and drug responses. Importantly, APC is uniquely well-suited to characterize variants of uncertain significance (VUS). By directly measuring the functional consequence of each VUS, APC can classify VUS as likely pathogenic or benign and guide therapeutic hypotheses. This approach mirrors precision strategies used in cystic fibrosis, where companies such as Vertex have developed variant-informed paths to modulator therapy by combining systematic functional testing with clinical data.
Rare diseases across ion channel families
As shown in the image above, rare diseases (defined as affecting fewer than 1 in ~2000 people) are found across all tissues and physiological types, and across all ion channel families. Below are representative examples showing how different channel families map to rare disease and where APC can potentially help:
- Voltage-gated sodium channels (SCN1A, SCN2A, SCN8A)
Manifest as severe developmental and epileptic encephalopathies; APC defined variant-specific gain-of-function versus loss-of-function effects will determine their definition and therapeutic direction. (Brunklaus et al., 2022); (Vanoye et al., 2024); (Clatot et al., 2025) - Voltage-gated calcium channels (CACNA1A – CACNA1E, CACNA1G, CACNA1H)
Familial hemiplegic migraine, Timothy syndrome, ataxias and neurodevelopmental disorders; complex splice isoform and trafficking defects require high-throughput functional assays. (Szymanowicz et al., 2024) - Voltage-gated potassium channels (KCNQ1, KCNH2, KCNMA1, KCNQ2)
Long QT syndromes and episodic movement disorders; APC enables rapid drug-safety and rescue screening towards therapeutic development. (Vanoye et al., 2022) - Ryanodine receptor (RYR2)
Catecholaminergic polymorphic ventricular tachycardia and associated ‘ryanopathies’; functional profiling of Ca²⁺-release defects supports targeted stabilizer drug discovery and development. (Sleiman et al., 2021) - Ligand-gated channels (GABA-A, NMDA, GlyR)
Developmental epilepsies and hyperekplexia; pharmacological profiling of VUS can reveal altered agonist or antagonist sensitivity. (Markus et al., 2020); (Vieira et al., 2021); (Mizzi & Blundell, 2025) - Purinergic and TRP channels (P2X, TRP)
Hereditary pain syndromes and dermatological disorders; APC combined with orthogonal read-outs help define channel gating under physiological stimuli. (Caseley et al., 2014; Fallah et al., 2022)