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KCNJ13 encodes the Kir7.1 inwardly rectifying potassium channel, which maintains ionic homeostasis in the retinal pigment epithelium. Heterozygous pathogenic variants in KCNJ13 cause snowflake vitreoretinal degeneration (SVD), an autosomal dominant disorder marked by vitreous degeneration, retinoschisis, and progressive risk of retinal detachment. The association between KCNJ13 and SVD is supported by multiple unrelated probands and concordant functional assays.
Five individuals from two unrelated families carry the recurrent missense variant c.484C>T (p.Arg162Trp), which resides in the conserved M2 transmembrane domain and disrupts channel function. Segregation of this variant across four affected relatives in a Swedish pedigree and identification in an independent highly myopic case establish strong genetic evidence (5 probands; PMID:35477418, PMID:36440807).
Functional studies using Xenopus laevis oocytes demonstrate that Kir7.1 p.Arg162Trp fails to form functional channels and exerts a dominant-negative effect on wild-type subunits, reducing K+ currents by ~83% without altering ion selectivity (PMID:23255580). This mechanism explains the autosomal dominant inheritance and aligns with the human SVD phenotype.
No conflicting reports have been published to date. The current variant spectrum for SVD remains limited to p.Arg162Trp, underscoring the need for continued genetic screening in atypical vitreoretinopathies.
In summary, abundant genetic segregation data and robust in vitro functional assays classify the KCNJ13–SVD association as Strong by ClinGen criteria. Awareness of p.Arg162Trp in diagnostic panels enables precise molecular diagnosis and informs exploration of channel-restorative therapies.
Gene–Disease AssociationStrong5 probands across two unrelated families, segregation in 4 affected relatives, concordant functional data Genetic EvidenceStrong5 heterozygous missense probands (c.484C>T) in 2 families; recurrent variant in conserved domain Functional EvidenceModerateDominant-negative channel dysfunction demonstrated in oocyte electrophysiology assays |