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Andersen-Tawil syndrome (ATS; [MONDO:0008222]) is an autosomal-dominant multisystem channelopathy caused by heterozygous variants in the KCNJ2 gene ([HGNC:6263]). Clinically, ATS presents with the triad of periodic paralysis (HP:0003768), ventricular arrhythmias (HP:0011675), and distinctive dysmorphic features such as micrognathia (HP:0000347) and short stature (HP:0004322). Initial linkage to KCNJ2 was demonstrated by mapping to 17q23 and identification of a D71V mutation with dominant-negative loss of Kir2.1 current in Xenopus oocytes ([PMID:11371347]). Subsequent cohort and family studies have consistently found KCNJ2 mutations in >29 unrelated ATS probands, with segregation in at least 19 affected relatives ([PMID:12796536]; [PMID:17119796]). The majority of pathogenic variants are missense changes affecting PIP₂-binding residues or the channel pore, with recurrent alleles such as c.652C>T (p.Arg218Trp) described in multiple families.
Genetic evidence supports an autosomal-dominant inheritance mode with occasional de novo and mosaic presentations. Across case series, >29 probands have carried KCNJ2 variants in >20 unrelated kindreds, with segregation of the variant in 19 affected family members ([PMID:12796536]). The variant spectrum includes 25+ missense mutations (e.g., c.652C>T (p.Arg218Trp)), nonsense, frameshift, and small deletions, as well as rare whole-gene deletions, indicating haploinsufficiency and dominant-negative effects. Several founder and recurrent variants (p.Arg218Trp, p.Gly144Ala, p.Thr75Met) have been described in ethnically diverse cohorts.
Functional assays across multiple systems demonstrate concordant loss of Kir2.1 function. Xenopus oocyte and mammalian cell patch-clamp experiments reveal that disease-associated missense mutations (e.g., p.Asp71His, p.Arg218Trp) abolish channel conductance and exert dominant-negative suppression of wild-type subunits ([PMID:11371347]; [PMID:12163457]). PIP₂ binding assays and yeast two-hybrid studies implicate defective membrane lipid interactions as a common pathogenic mechanism ([PMID:12796536]; [PMID:17568571]). Confocal imaging confirms normal trafficking for some mutants (T74A, G144A) and ER retention for truncating alleles (S369X), correlating with phenotype severity.
Despite strong overall support, incomplete penetrance and phenotypic variability are noted. Some mutation carriers exhibit isolated cardiac arrhythmias without paralysis or dysmorphia, and mosaicism has been reported in asymptomatic parents ([PMID:24635491]). Variants originally classified as ATS-causing have been reobserved in long QT syndrome and CPVT cohorts, underlining the need for careful variant interpretation ([PMID:21875779]; [PMID:19843922]). However, these findings do not negate the KCNJ2–ATS association but highlight allelic heterogeneity.
In summary, over two decades of genetic and experimental studies conclusively establish KCNJ2 as the causative gene for Andersen-Tawil syndrome, mediating disease via dominant-negative loss of Kir2.1 inward rectifier function and impaired PIP₂ interactions. Clinical genetic testing for KCNJ2 variants is critical for definitive diagnosis, family counseling, and tailored management of arrhythmias and periodic paralysis. Key take-home: Identification of a pathogenic KCNJ2 variant confirms ATS, guiding surveillance for life-threatening ventricular arrhythmias and episodic paralysis.
Gene–Disease AssociationDefinitiveMultiple independent studies over >20 years across >29 unrelated probands, familial segregation, and consistent functional evidence Genetic EvidenceStrong29 probands in >20 families with segregation in 19 relatives ([PMID:12796536]) Functional EvidenceStrongIn vitro and in vivo assays show dominant-negative loss of Kir2.1 current concordant with human phenotype ([PMID:11371347]; [PMID:12163457]) |