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Familial atrial fibrillation (FAF) has been linked to autosomal dominant gain-of-function mutations in KCNQ1, encoding the cardiac slow delayed rectifier potassium channel (IKs). Two unrelated missense variants have been reported in probands with early-onset lone AF, with segregation and functional assays supporting pathogenicity.
In the AF-324 kindred, a heterozygous c.625T>C (p.Ser209Pro) variant co-segregated with AF in 6 of 14 family members (5 additional affected relatives) and showed linkage to marker D11S4088 within KCNQ1 ([PMID:19632626]). Affected individuals had a mean onset age of 32 years and a hyperpolarizing shift in voltage activation, accelerated channel opening, slowed deactivation, and a constitutive IKs current, consistent with a gain-of-function mechanism.
A second missense variant, c.691C>T (p.Arg231Cys), originally identified in LQT1 families, was observed in a FAF proband without other AF-linked gene mutations. In HEK293 cells coexpressed with KCNE1, R231C-IKs exhibited both constitutive activity and reduced peak current, demonstrating mixed gain- and loss-of-function properties that can predispose to AF ([PMID:20850564]).
Genetically, FAF-associated KCNQ1 variants are exclusively missense, with no loss-of-function truncations reported in AF. Inheritance is autosomal dominant, and segregation has been shown in one large kindred. No recurrent or founder AF-specific alleles have yet been described, and population frequencies are negligible.
Functional studies in heterologous systems consistently show that AF-linked KCNQ1 mutations alter gating to increase net IKs current at atrial resting potentials, shortening the atrial action potential and promoting reentrant arrhythmias. These data establish a clear gain-of-function mechanism for AF pathogenesis.
Overall, limited genetic evidence (two unrelated probands, segregation in one family with 5 additional affected relatives) and moderate functional data support a Limited clinical validity classification for KCNQ1 in familial AF. KCNQ1 genotyping can aid diagnosis in early-onset AF families and inform risk-stratified management strategies.
Gene–Disease AssociationLimitedTwo unrelated probands with AF, segregation in one family (5 additional affected relatives), functional concordance Genetic EvidenceLimitedAD inheritance; 2 missense variants in 2 probands; segregation in one kindred; no truncating variants Functional EvidenceModerateHeterologous expression studies show hyperpolarizing shift, accelerated activation, slowed deactivation, and constitutive IKs current consistent with gain-of-function |