KCNJ13

Inheritance Pattern: AD

Disease ID:MONDO:0008663

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0008663

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0013613

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0018998

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013613

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0008663

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013613

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0019118

Submitter: ClinGen

The *KCNJ13* gene was first reported in relation to autosomal recessive Leber congenital amaurosis in 2011 (Sergouniotis et al., PMID: 21763485), following a 2008 study linking the gene to autosomal dominant cases of snowflake vitreoretinal degeneration (Hejtmancik et al., PMID: 18179896). Cases reported as Leber congenital amaurosis 16 or vitreoretinal dystrophy generally had onset ranging from birth to early adulthood and showed severely decreased electroretinogram responses from both rods and cones, severe decrease in central visual acuity and constriction of peripheral visual field, nyctalopia, nystagmus, early onset cataracts, moderate myopia, fibrosis over the optic discs, and abnormalities of the retinal vasculature such as retinal arteriolar constriction, retinal neovascularization, and/or vitreous hemorrhage. Cases described as snowflake vitreoretinal degeneration exhibited some similar features such as early onset cataracts, moderate myopia, and dysmorphic optic discs, but generally showed onset in the second decade of life or later. They additionally showed distinct features such as snowflake-like retinal deposits, focal retinal pigment epithelium degeneration, reduced macular function, reduced scotopic b-wave, corneal guttae, and increased risk of retinal detachment. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, cases of snowflake vitreoretinal degeneration were found to be distinguishable by both their molecular mechanism (a monoallelic missense variant p.Arg162Trp resulting in nonselective cation current causing cell depolarization) and mode of inheritance (autosomal dominant), in comparison to the biallelic loss-of-function mechanism of autosomal recessive Leber congenital amaurosis 16. While the two conditions share some overlapping phenotypic features, heterozygous carriers from recessive families have so far been found to be unaffected (PMID: 21763485, PMID: 35477418). Therefore, cases of Leber congenital amaurosis or other retinopathies caused by biallelic *KCNJ13* variants have been recommended for splitting into the present curation under a disease entity referred to as KCNJ13-related recessive retinopathy. *KCNJ13* will be curated separately for autosomal dominant snowflake vitreoretinal degeneration. This curation has scored eight suspected disease-causing variants (five missense and three nonsense), which have been collectively reported in seven probands in six publications (PMID: 21763485, PMID: 25921210, PMID: 25475713, PMID: 31647904, PMID: 27203561, PMID: 32783370). All probands included in this curation harbored two variant alleles within the *KCNJ13* locus, with only one being compound heterozygous (PMID: 27203561). Six probands were homozygous with two known to have consanguineous parents (PMID: 21763485, PMID: 25475713). The mechanism of pathogenicity appears to be biallelic loss of function, characterized in some cases by nonsense variants predicted to trigger absence or decrease in the amount of the gene product (PMID: 21763485, PMID: 25475713, PMID: 27203561). These publications did not contain families with a sufficient number of affected family members to evaluate segregation evidence. A small number of additional cases were available, but were not included in the curation as they shared genotypes with previously scored probands (PMID: 25475713, PMID: 31647904). This gene-disease association is also supported by experimental evidence that *KCNJ13* is highly expressed in the retinal pigment epithelium (RPE), and to a lesser degree in retina and small intestine (PMID: 30239781). *KCNJ13* encodes a potassium channel (also known as Kir7.1) that localizes to long apical membrane extensions or microvilli of RPE cells (PMID: 28878288) and allows intracellular potassium ions to flow out into the subretinal space to maintain normal potassium levels during photoreception (PMID: 23255580). Biallelic disruption of the *KCNJ13* ortholog in *obetd15* zebrafish results in late-onset retinal degeneration, retinal thinning with loss of the RPE and photoreceptor layers, and vascular abnormalities including wider retinal blood vessels and fibrotic material at the optic discs (PMID: 31647904). While mice with biallelic *Kcnj13* knockout are not viable, conditional knockout in RPE cells results in severe retinal degeneration with loss of the photoreceptor layer and abnormal RPE morphology and function, extinguished electroretinogram a-waves and b-waves, and some attenuation of retinal blood vessels (PMID: 35096838). Mice harboring a nonsense variant from a human patient in RPE cells showed reduced amplitude in the electroretinogram c-wave originating from the RPE that could be partially rescued by subretinal injection of sgRNA to restore the wild-type allele through CRISPR/Cas9-based editing (PMID: 37561581). Additional data from model organisms and rescue experiments were available but not included in the curation, as the maximum scoring from this evidence type had already been reached. In summary, *KCNJ13* has a Definitive association with KCNJ13-related recessive retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on April 3rd, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0008663

Submitter: ClinGen

The *KCNJ13* gene was first reported in relation to autosomal dominant cases of snowflake vitreoretinal degeneration in 2008 (Hejtmancik et al., PMID: 18179896). Affected individuals have a phenotypic spectrum that includes snowflake-like retinal deposits, focal retinal pigment epithelium degeneration, reduced macular function, reduced scotopic b-wave, corneal guttae, early onset cataracts, moderate myopia, dysmorphic optic discs, and/or increased risk of retinal detachment, with onset generally in the second decade of life or later. *KCNJ13* variants have separately been reported in relation to autosomal recessive Leber congenital amaurosis in 2011 (Sergouniotis et al., PMID: 21763485). Some features overlapped with the dominant cases, including early onset cataracts and moderate myopia, however, onset ranged from birth to early adulthood and distinguishing features included severely decreased electroretinogram responses from both rods and cones, severe decrease in central visual acuity and constriction of peripheral visual field, nyctalopia, nystagmus, fibrosis over the optic discs, and abnormalities of the retinal vasculature such as retinal arteriolar constriction, retinal neovascularization, and/or vitreous hemorrhage. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, cases of snowflake vitreoretinal degeneration were found to be distinguishable by both their molecular mechanism (a monoallelic missense variant p.Arg162Trp resulting in nonselective cation current causing cell depolarization) and mode of inheritance (autosomal dominant), in comparison to the biallelic loss-of-function mechanism of autosomal recessive Leber congenital amaurosis 16. While the two conditions share some overlapping phenotypic features, heterozygous carriers from recessive families have so far been found to be unaffected (PMID: 21763485, PMID: 35477418). Therefore, *KCNJ13*-related vitreoretinopathy and *KCNJ13*-related recessive retinopathy are considered two disease entities and curated separately. This curation has scored one suspected disease-causing variant (the missense variant p.Arg162Trp), which was reported in three different probands in three publications (PMID: 18179896, PMID: 36440807, PMID: 35477418). All probands were heterozygous, with two known to have affected family members sharing the same genotype (PMID: 18179896, PMID: 35477418). The mechanism of pathogenicity appears to be dominant negative, with the missense variant resulting in nonselective cation current causing cell depolarization (PMID: 18179896, PMID: 23255580, PMID: 23977131, PMID: 33219695). Two publications contained families with multiple affected family members and were evaluated for segregation evidence (PMID: 18179896, PMID: 35477418). This gene-disease association is also supported by experimental evidence that *KCNJ13* is highly expressed in the retinal pigment epithelium (RPE), and to a lesser degree in retina and small intestine (PMID: 30239781). *KCNJ13* encodes a potassium channel (also known as Kir7.1) that localizes to long apical membrane extensions or microvilli of RPE cells (PMID: 28878288) and allows intracellular potassium ions to flow out into the subretinal space to maintain normal potassium levels during photoreception (PMID: 23255580). Functional studies exogenously expressing the p.Arg162Trp variant in Chinese hamster ovary (CHO) cells, HEK293T cells, or *Xenopus* oocytes have shown that the variant has localizes to the cell surface normally and interacts with the wild-type protein, but causes reduced channel activity, including when co-expressed with the wild-type protein (PMID: 23255580, PMID: 23977131, PMID: 33219695). The variant may disrupt part of a phosphoinositide binding site that is essential for stabilizing the open state of KCNJ13 (PMID: 33219695). In summary, *KCNJ13* has Moderate evidence of association with *KCNJ13*-related vitreoretinopathy. This has been repeatedly demonstrated in both research and diagnostic settings and has been upheld over time without the emergence of contradictory evidence, however, additional case-level evidence will be required to reach a more definitive classification. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on July 3rd, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0008663

Submitter: G2P