Leber congenital amaurosis 16 (LCA16) is an autosomal recessive early-onset severe retinal dystrophy caused by biallelic loss-of-function variants in KCNJ13, which encodes Kir7.1, an inwardly rectifying potassium channel subunit that sits in the apical membrane of the retinal pigment epithelium (RPE). Unlike most forms of LCA, the primary lesion is in the RPE rather than in the photoreceptors. Loss of Kir7.1 conductance leaves the RPE unable to set its membrane potential and to buffer subretinal potassium, and patient-derived and knockout RPE show reduced phagocytosis of photoreceptor outer segments, secondary mitochondrial changes, and vulnerability to oxidative stress. The overlying rods and cones then degenerate. Affected individuals have nystagmus and severe visual loss from infancy, night blindness, and a distinctive fundus with dense clumped or nummular pigment at the level of the RPE, macular atrophy, optic disc pallor and vessel attenuation. Juvenile or early-adult cataract is common, and two siblings homozygous for an M2-domain missense allele developed retinal neovascularization and vitreous hemorrhage in adolescence. Heterozygous carriers are clinically unaffected. Specific dominant KCNJ13 alleles cause a different disorder, snowflake vitreoretinal degeneration. No disease-specific therapy exists; gene augmentation, base editing and nonsense-suppression approaches have rescued channel function in patient-derived RPE and in mouse models.
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Conditions with similar clinical presentations that must be differentiated from Leber Congenital Amaurosis 16:
name: Leber Congenital Amaurosis 16
creation_date: "2026-10-15T00:00:00Z"
category: Mendelian
description: >-
Leber congenital amaurosis 16 (LCA16) is an autosomal recessive early-onset
severe retinal dystrophy caused by biallelic loss-of-function variants in
KCNJ13, which encodes Kir7.1, an inwardly rectifying potassium channel subunit
that sits in the apical membrane of the retinal pigment epithelium (RPE). Unlike
most forms of LCA, the primary lesion is in the RPE rather than in the
photoreceptors. Loss of Kir7.1 conductance leaves the RPE unable to set its
membrane potential and to buffer subretinal potassium, and patient-derived and
knockout RPE show reduced phagocytosis of photoreceptor outer segments,
secondary mitochondrial changes, and vulnerability to oxidative stress. The
overlying rods and cones then degenerate. Affected individuals have nystagmus
and severe visual loss from infancy, night blindness, and a distinctive fundus
with dense clumped or nummular pigment at the level of the RPE, macular atrophy,
optic disc pallor and vessel attenuation. Juvenile or early-adult cataract is
common, and two siblings homozygous for an M2-domain missense allele developed
retinal neovascularization and vitreous hemorrhage in adolescence. Heterozygous
carriers are clinically unaffected. Specific dominant KCNJ13 alleles cause a
different disorder, snowflake vitreoretinal degeneration. No disease-specific
therapy exists; gene augmentation, base editing and nonsense-suppression
approaches have rescued channel function in patient-derived RPE and in mouse
models.
notes: >-
The entry is anchored on MONDO:0013613 (OMIM 614186) and KCNJ13 (hgnc:6259).
KCNJ13-LCA accounts for an unknown or less than 1% share of LCA/EOSRD
(PMID:40294858), and the published literature consists of fewer than a dozen
families, so no phenotype carries a frequency band.
ClinGen classifies KCNJ13 as Definitive for autosomal recessive "inherited
retinal dystrophy" (MONDO:0019118) and Moderate for autosomal dominant snowflake
vitreoretinal degeneration (MONDO:0008663). Neither assertion is for
MONDO:0013613, so no gene_disease_validity tier is recorded on the genetic
block.
The mouse and human RPE data disagree on whether Kir7.1-deficient RPE cells
survive. In CRISPR mosaic mice the Kcnj13-null RPE cells survived while the
photoreceptors above them degenerated (PMID:25666713); in human iPSC-RPE the
knockout cells died under oxidative stress (PMID:36413373). Both observations
are curated, on the RPE oxidative-stress node.
The GeneReviews chapter that covers this disease is the nonsyndromic LCA/EOSRD
overview (PMID:30285347). Its PubMed record has no clinical abstract, so it is
tagged in references but no phenotype quotes it.
disease_term:
preferred_term: Leber congenital amaurosis 16
term:
id: MONDO:0013613
label: Leber congenital amaurosis 16
synonyms:
- LCA16
- Leber congenital amaurosis type 16
- KCNJ13-related Leber congenital amaurosis
- KCNJ13 retinal dystrophy
parents:
- Leber Congenital Amaurosis
- Inherited Retinal Dystrophy
references:
- reference: PMID:30285347
title: Nonsyndromic Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview.
tags:
- GeneReviews
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Disease requires two loss-of-function KCNJ13 alleles, either homozygous
(often in consanguineous families) or compound heterozygous. Heterozygous
carriers have no ocular disease, and a truncating allele does not suppress
wild-type channel function when the two are co-expressed.
evidence:
- reference: PMID:21763485
reference_title: "Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Examination of heterozygotes revealed no ocular disease."
explanation: >-
Heterozygous relatives of the homozygous probands are unaffected, as
expected for recessive inheritance.
- reference: PMID:25921210
reference_title: "A Novel KCNJ13 Nonsense Mutation and Loss of Kir7.1 Channel Function Causes Leber Congenital Amaurosis (LCA16)."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Coexpression of the mutant and wild-type channel has no negative influence on the wild-type channel function, consistent with the normal clinical phenotype of carrier individuals."
explanation: >-
The truncated channel is not dominant negative, which explains why one
wild-type allele is enough.
- reference: PMID:27203561
reference_title: "LEBER CONGENITAL AMAUROSIS WITH LARGE RETINAL PIGMENT CLUMPS CAUSED BY COMPOUND HETEROZYGOUS MUTATIONS IN KCNJ13."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient was compound heterozygous for new mutations in KCNJ13 which encodes the Kir 7.1 potassium channel, c.314G>T (p.Ser105Ile) in exon 2 and c.655C>T (p.Gln219*) in exon 3."
explanation: >-
Compound heterozygosity, as well as homozygosity, causes the disease.
prevalence:
- population: Worldwide reported literature
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
No population prevalence estimate exists. A tertiary-centre series groups
KCNJ13 with genes that account for an unknown or less than 1% of all
LCA/EOSRD cases.
evidence:
- reference: PMID:40294858
reference_title: "Clinical Characteristics of Patients With Less Common Causes of Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Review of clinical notes, ophthalmic images, and genetic testing results of 19 patients with disease-causing variants in genes that represent an unknown or <1% of all LCA/EOSRD cases: ALMS1, CABP4, KCNJ13, and OTX2."
explanation: >-
Places KCNJ13 among the genes that account for less than 1% of LCA/EOSRD,
supporting an ultra-rare classification.
pathophysiology:
- name: Biallelic KCNJ13 Loss-of-Function Variants
biological_scale: MOLECULAR
description: >-
Two damaging KCNJ13 alleles are inherited. The published alleles include
nonsense variants (p.Trp53Ter, p.Arg166Ter, p.Gln219Ter) and missense
variants (p.Ser105Ile, p.Ile120Thr, p.Thr153Ile, p.Leu241Pro). Truncating
alleles mislocalize the channel; the M2-domain missense allele p.Thr153Ile
reaches the membrane but conducts almost no potassium.
genes:
- preferred_term: KCNJ13
term:
id: hgnc:6259
label: KCNJ13
molecular_functions:
- preferred_term: inward rectifier potassium channel activity
term:
id: GO:0005242
label: inward rectifier potassium channel activity
modifier: DECREASED
genetic_context:
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
evidence:
- reference: PMID:21763485
reference_title: "Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A combination of homozygosity mapping and exome sequencing identifies a homozygous nonsense mutation, c.496C>T (p.Arg166X), in a gene, KCNJ13, encoding a potassium channel subunit Kir7.1."
explanation: >-
Discovery of a homozygous KCNJ13 nonsense allele as the cause of LCA.
- reference: PMID:25921210
reference_title: "A Novel KCNJ13 Nonsense Mutation and Loss of Kir7.1 Channel Function Causes Leber Congenital Amaurosis (LCA16)."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We have determined that the mutation results in a severe truncation of the Kir7.1 C-terminus, alters protein localization, and disrupts potassium currents."
explanation: >-
Shows that a patient nonsense allele abolishes channel function.
downstream:
- target: Loss of Kir7.1 Potassium Conductance in the RPE
causal_link_type: DIRECT
description: >-
Truncated, mislocalized or non-conducting Kir7.1 subunits leave the RPE
apical membrane without the channel.
evidence:
- reference: PMID:35584325
reference_title: "Kir7.1 disease mutant T153I within the inner pore affects K(+) conduction."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Whole cell patch-clamp recordings and chord conductance analyses revealed that the T153I mutant channel had negligible K+ conductance and failed to hyperpolarize the membrane potential."
explanation: >-
A missense patient allele that is correctly localized still abolishes
potassium conductance.
- name: Loss of Kir7.1 Potassium Conductance in the RPE
biological_scale: CELLULAR
description: >-
Kir7.1 is the main potassium conductance of the RPE apical membrane facing
the photoreceptors. Patient-derived RPE carrying p.Trp53Ter lacks a
functional Kir7.1 current and has a depolarized membrane potential, which
impairs potassium recycling into the subretinal space.
cell_types:
- preferred_term: retinal pigment epithelial cell
term:
id: CL:0002586
label: retinal pigment epithelial cell
molecular_functions:
- preferred_term: inward rectifier potassium channel activity
term:
id: GO:0005242
label: inward rectifier potassium channel activity
modifier: DECREASED
biological_processes:
- preferred_term: potassium ion transmembrane transport
term:
id: GO:0071805
label: potassium ion transmembrane transport
modifier: DECREASED
locations:
- preferred_term: retinal pigment epithelium
term:
id: UBERON:0001782
label: pigmented layer of retina
evidence:
- reference: PMID:30686507
reference_title: "Gene Augmentation and Readthrough Rescue Channelopathy in an iPSC-RPE Model of Congenital Blindness."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We found that the LCA16 hiPSC-RPE cells had normal morphology but did not express a functional Kir7.1 channel and were unable to demonstrate normal physiology."
explanation: >-
RPE derived from a patient with LCA16 lacks a working Kir7.1 channel.
- reference: PMID:30686507
reference_title: "Gene Augmentation and Readthrough Rescue Channelopathy in an iPSC-RPE Model of Congenital Blindness."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "After readthrough drug treatment, the LCA16 hiPSC cells were hyperpolarized by 30 mV, and the Kir7.1 current was restored."
explanation: >-
Restoring the channel hyperpolarizes the cells by 30 mV, which implies
that the untreated patient RPE is depolarized because Kir7.1 is missing.
downstream:
- target: Impaired RPE Phagocytosis of Photoreceptor Outer Segments
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Kir7.1-null RPE takes up and clears fewer photoreceptor outer segments.
How the loss of potassium conductance impairs phagocytosis is not known.
evidence:
- reference: PMID:32437550
reference_title: "KCNJ13 Gene Deletion Impairs Cell Alignment and Phagocytosis in Retinal Pigment Epithelium Derived from Human-Induced Pluripotent Stem Cells."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We suggest that Kir7.1 is required for phagocytosis of POSs by RPE cells and that impaired phagocytosis in the absence of Kir7.1 would be involved in the retinal degeneration found in LCA16."
explanation: >-
Links absence of Kir7.1 to impaired outer-segment phagocytosis in
human RPE.
- target: RPE Oxidative Stress and Cell Death
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Kir7.1-knockout human RPE is more vulnerable to oxidative stress and
dies.
evidence:
- reference: PMID:36413373
reference_title: "Protrusion of KCNJ13 Gene Knockout Retinal Pigment Epithelium Due to Oxidative Stress-Induced Cell Death."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We suggest that in the absence of the Kir.7.1 potassium channel, human RPE cells are vulnerable to oxidative stress and ultimately die."
explanation: >-
Connects loss of Kir7.1 to oxidative-stress vulnerability and death of
human RPE.
- target: Loss of RPE Support for Photoreceptor Survival
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Mosaic mice show that photoreceptors degenerate only above RPE cells
lacking Kir7.1, so the requirement is RPE-autonomous.
evidence:
- reference: PMID:25666713
reference_title: "CRISPR-engineered mosaicism rapidly reveals that loss of Kcnj13 function in mice mimics human disease phenotypes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "These results suggest that KCNJ13 expression is required for RPE cells to maintain photoreceptor survival."
explanation: >-
Mosaic Kcnj13 loss in mouse RPE shows that the channel is needed in
the RPE for photoreceptor survival.
- name: Impaired RPE Phagocytosis of Photoreceptor Outer Segments
biological_scale: CELLULAR
description: >-
Kir7.1-deficient RPE takes up and degrades fewer shed photoreceptor outer
segments. In kcnj13 mutant zebrafish, phagosomes accumulate in the RPE
before any retinal degeneration is visible.
cell_types:
- preferred_term: retinal pigment epithelial cell
term:
id: CL:0002586
label: retinal pigment epithelial cell
biological_processes:
- preferred_term: phagocytosis of photoreceptor outer segments
term:
id: GO:0006909
label: phagocytosis
modifier: DECREASED
evidence:
- reference: PMID:32437550
reference_title: "KCNJ13 Gene Deletion Impairs Cell Alignment and Phagocytosis in Retinal Pigment Epithelium Derived from Human-Induced Pluripotent Stem Cells."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "However, phagocytic activity and expression of phagocytosis-related genes in the KCNJ13-null hiPSC-RPE cells were significantly reduced compared to those of WT."
explanation: >-
Direct measurement of reduced outer-segment phagocytosis in KCNJ13-null
human RPE.
- reference: PMID:30846767
reference_title: "Phagosomal and mitochondrial alterations in RPE may contribute to KCNJ13 retinopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Electron microscopy of the obelixtd15 retinal pigment epithelium (RPE) uncovered reduced phagosome clearance and increased mitochondrial number and size prior any signs of retinal degeneration."
explanation: >-
Reduced phagosome clearance precedes degeneration in the kcnj13 mutant
zebrafish.
downstream:
- target: Secondary RPE Mitochondrial Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The zebrafish study proposes that the phagosome defect comes first and
the mitochondrial change follows. That ordering is inferred from timing
in one model.
evidence:
- reference: PMID:30846767
reference_title: "Phagosomal and mitochondrial alterations in RPE may contribute to KCNJ13 retinopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We propose that the retinal disease in this model is primarily a failure of phagosome physiology with a secondary mitochondrial dysfunction."
explanation: >-
States the proposed order: phagosome failure, then mitochondrial
dysfunction.
- name: Secondary RPE Mitochondrial Dysfunction
biological_scale: CELLULAR
mechanism_confidence: PROVISIONAL
description: >-
Mutant zebrafish RPE has more and larger mitochondria and lower ATP, with
expression changes in mitochondrial and stress genes. This has only been
shown in zebrafish.
cell_types:
- preferred_term: retinal pigment epithelial cell
term:
id: CL:0002586
label: retinal pigment epithelial cell
biological_processes:
- preferred_term: mitochondrion organization
term:
id: GO:0007005
label: mitochondrion organization
modifier: ABNORMAL
evidence:
- reference: PMID:30846767
reference_title: "Phagosomal and mitochondrial alterations in RPE may contribute to KCNJ13 retinopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "At 6 and 12 months, ATP levels were found to be reduced along with increased expression of glial fibrillary acidic protein and heat shock protein 60."
explanation: >-
Reduced ATP and stress-protein induction in the mutant retina.
downstream:
- target: Loss of RPE Support for Photoreceptor Survival
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Proposed contribution of RPE organelle dysfunction to photoreceptor
degeneration.
evidence:
- reference: PMID:30846767
reference_title: "Phagosomal and mitochondrial alterations in RPE may contribute to KCNJ13 retinopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Our findings suggest that alterations in the RPE and photoreceptor cellular organelles may contribute to KCNJ13-related retinal degeneration and provide a therapeutic target."
explanation: >-
The authors propose, rather than demonstrate, that these organelle
changes contribute to degeneration.
- name: RPE Oxidative Stress and Cell Death
biological_scale: CELLULAR
description: >-
KCNJ13-knockout human iPSC-RPE shows raised oxidative-stress gene
expression and glutathione, increased cell death, and dying cells that
aggregate and protrude from the epithelial sheet. In mosaic mice, by
contrast, Kcnj13-null RPE cells survived, so whether RPE death occurs in
patients is not settled.
cell_types:
- preferred_term: retinal pigment epithelial cell
term:
id: CL:0002586
label: retinal pigment epithelial cell
biological_processes:
- preferred_term: response to oxidative stress
term:
id: GO:0006979
label: response to oxidative stress
modifier: INCREASED
- preferred_term: cell death
term:
id: GO:0008219
label: cell death
modifier: INCREASED
evidence:
- reference: PMID:36413373
reference_title: "Protrusion of KCNJ13 Gene Knockout Retinal Pigment Epithelium Due to Oxidative Stress-Induced Cell Death."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The KCNJ13-deficient RPE showed increased expression levels of oxidative stress-related genes and total glutathione levels."
explanation: >-
Oxidative-stress response is raised in Kir7.1-deficient human RPE.
- reference: PMID:36413373
reference_title: "Protrusion of KCNJ13 Gene Knockout Retinal Pigment Epithelium Due to Oxidative Stress-Induced Cell Death."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Furthermore, t-BHP induced a significant increase in cell death and GSSG levels in the KO RPE."
explanation: >-
An oxidant challenge kills more knockout than wild-type RPE cells.
- reference: PMID:25666713
reference_title: "CRISPR-engineered mosaicism rapidly reveals that loss of Kcnj13 function in mice mimics human disease phenotypes."
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: "We found that RPE cells lacking KCNJ13 protein still survive but overlying photoreceptors exhibit cell degeneration."
explanation: >-
In mouse, Kcnj13-null RPE cells survive, which contradicts RPE death as
a necessary step. This conflicts with the human iPSC-RPE result above.
downstream:
- target: RPE Disorganization and Pigment Clumping
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Dying RPE cells aggregate and protrude from the sheet, a plausible basis
for the clumped pigment seen clinically.
evidence:
- reference: PMID:36413373
reference_title: "Protrusion of KCNJ13 Gene Knockout Retinal Pigment Epithelium Due to Oxidative Stress-Induced Cell Death."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "The dying/dead cells form aggregates and protrude from the surviving KCNJ13-deficient RPE sheet."
explanation: >-
Describes RPE cell aggregation in culture; the link to the clinical
pigment clumps is an inference.
- name: RPE Disorganization and Pigment Clumping
biological_scale: TISSUE
description: >-
The RPE becomes disorganized, with large clumped pigment deposits at the
RPE level, most dense over the posterior pole. This fundus appearance is
distinctive enough to suggest KCNJ13 before testing.
locations:
- preferred_term: retinal pigment epithelium
term:
id: UBERON:0001782
label: pigmented layer of retina
evidence:
- reference: PMID:27203561
reference_title: "LEBER CONGENITAL AMAUROSIS WITH LARGE RETINAL PIGMENT CLUMPS CAUSED BY COMPOUND HETEROZYGOUS MUTATIONS IN KCNJ13."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "KCNJ13 mutations are responsible for early-onset retinal dystrophy, featuring remarkable clumpy pigment deposits at the level of the retinal pigment epithelium, suggesting dysfunction and disorganization of this tissue."
explanation: >-
Clinical description of RPE-level pigment clumping and its
interpretation as RPE disorganization.
downstream:
- target: Nummular retinal pigmentation
causal_link_type: DIRECT
description: >-
RPE disorganization appears clinically as clumped or nummular pigment.
evidence:
- reference: PMID:27203561
reference_title: "LEBER CONGENITAL AMAUROSIS WITH LARGE RETINAL PIGMENT CLUMPS CAUSED BY COMPOUND HETEROZYGOUS MUTATIONS IN KCNJ13."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There were clumpy pigment deposits mostly in macular area, causing an uneven line of retinal pigment epithelium on spectral domain optical coherence tomography."
explanation: >-
Links the clinical pigment deposits to an uneven RPE line on OCT.
- target: Macular atrophy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Loss of RPE integrity at the posterior pole is accompanied by macular
atrophy.
evidence:
- reference: PMID:31647904
reference_title: "Missense variants in the conserved transmembrane M2 protein domain of KCNJ13 associated with retinovascular changes in humans and zebrafish."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "with areas of nummular pigment at the level of the RPE, especially over the posterior pole, macular atrophy and optic disc pallor with retinal vessel attenuation"
explanation: >-
Macular atrophy occurs together with RPE-level pigment changes at the
posterior pole in KCNJ13-LCA.
- name: Loss of RPE Support for Photoreceptor Survival
biological_scale: TISSUE
description: >-
Rods and cones degenerate above Kir7.1-deficient RPE. Mice lacking Kcnj13
only in the RPE show progressive outer nuclear layer thinning and reduced
light responses, and in patients both rod and cone pathways fail early.
cell_types:
- preferred_term: retinal rod cell
term:
id: CL:0000604
label: retinal rod cell
- preferred_term: retinal cone cell
term:
id: CL:0000573
label: retinal cone cell
biological_processes:
- preferred_term: photoreceptor cell maintenance
term:
id: GO:0045494
label: photoreceptor cell maintenance
modifier: DECREASED
evidence:
- reference: PMID:30009826
reference_title: "Conditional loss of Kcnj13 in the retinal pigment epithelium causes photoreceptor degeneration."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Furthermore, our findings show that widespread loss of Kcnj13 in the RPE leads to severe and progressive thinning of the outer nuclear layer and a reduced response to light."
explanation: >-
RPE-restricted loss of Kcnj13 is enough to cause photoreceptor loss.
- reference: PMID:21763485
reference_title: "Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All have a distinct and unusual retinal appearance and a similar early onset of visual loss, suggesting both impaired retinal development and progressive retinal degeneration, involving both rod and cone pathways."
explanation: >-
Patients show early rod and cone dysfunction with progressive
degeneration.
downstream:
- target: Severely reduced visual acuity
causal_link_type: DIRECT
description: Photoreceptor loss produces severe visual loss from infancy.
evidence:
- reference: PMID:40294858
reference_title: "Clinical Characteristics of Patients With Less Common Causes of Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Poorer vision was seen earliest in patients with ALMS1 and KCNJ13, with mean visual acuities of 2.2 and 2.8 logMAR in the second decade of life."
explanation: >-
Severe acuity loss in KCNJ13 patients by the second decade.
- target: Abnormal full-field electroretinogram
causal_link_type: DIRECT
description: Rod and cone dysfunction is recorded as a severely reduced ERG.
evidence:
- reference: PMID:25475713
reference_title: "A distinct vitreo-retinal dystrophy with early-onset cataract from recessive KCNJ13 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "electroretinography revealed severe cone-rod dysfunction, with only subnormal scotopic tracings recordable in both eyes"
explanation: >-
ERG shows severe photoreceptor dysfunction in a homozygous patient.
- target: Nyctalopia
causal_link_type: DIRECT
description: Rod dysfunction causes night blindness.
evidence:
- reference: PMID:40294858
reference_title: "Clinical Characteristics of Patients With Less Common Causes of Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "nyctalopia was observed in KCNJ13 and OTX2"
explanation: Night blindness is reported in KCNJ13 patients.
- target: Nystagmus
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Sensory nystagmus follows from profound visual loss in infancy.
evidence:
- reference: PMID:25475713
reference_title: "A distinct vitreo-retinal dystrophy with early-onset cataract from recessive KCNJ13 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A 12-year-old Saudi Arabian girl with nystagmus since birth was referred because of recent decreased vision."
explanation: >-
Nystagmus present from birth in a homozygous KCNJ13 patient.
- target: Optic disc pallor
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Optic disc pallor accompanies advanced outer-retinal degeneration.
evidence:
- reference: PMID:31647904
reference_title: "Missense variants in the conserved transmembrane M2 protein domain of KCNJ13 associated with retinovascular changes in humans and zebrafish."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "with areas of nummular pigment at the level of the RPE, especially over the posterior pole, macular atrophy and optic disc pallor with retinal vessel attenuation"
explanation: >-
Disc pallor is part of the characteristic KCNJ13-LCA fundus.
- target: Attenuation of retinal blood vessels
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Vessel attenuation accompanies the retinal degeneration.
evidence:
- reference: PMID:31647904
reference_title: "Missense variants in the conserved transmembrane M2 protein domain of KCNJ13 associated with retinovascular changes in humans and zebrafish."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "with areas of nummular pigment at the level of the RPE, especially over the posterior pole, macular atrophy and optic disc pallor with retinal vessel attenuation"
explanation: >-
Vessel attenuation is part of the characteristic KCNJ13-LCA fundus.
phenotypes:
- category: Ophthalmological
name: Severely reduced visual acuity
description: >-
Visual loss begins in infancy and is severe; reported acuities range from
about 0.7 logMAR to hand motion or no light perception.
phenotype_term:
preferred_term: Severely reduced visual acuity
term:
id: HP:0001141
label: Severely reduced visual acuity
onset:
onset_category: INFANTILE
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:40294858
reference_title: "Clinical Characteristics of Patients With Less Common Causes of Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Poorer vision was seen earliest in patients with ALMS1 and KCNJ13, with mean visual acuities of 2.2 and 2.8 logMAR in the second decade of life."
explanation: Severe acuity loss in KCNJ13 patients.
- reference: PMID:21763485
reference_title: "Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All have a distinct and unusual retinal appearance and a similar early onset of visual loss"
explanation: Early onset of visual loss in all three original patients.
- category: Ophthalmological
name: Nystagmus
description: Nystagmus is present from birth or early childhood.
phenotype_term:
preferred_term: Nystagmus
term:
id: HP:0000639
label: Nystagmus
evidence:
- reference: PMID:25475713
reference_title: "A distinct vitreo-retinal dystrophy with early-onset cataract from recessive KCNJ13 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A 12-year-old Saudi Arabian girl with nystagmus since birth was referred because of recent decreased vision."
explanation: Nystagmus from birth in a homozygous p.Ile120Thr patient.
- reference: PMID:27203561
reference_title: "LEBER CONGENITAL AMAUROSIS WITH LARGE RETINAL PIGMENT CLUMPS CAUSED BY COMPOUND HETEROZYGOUS MUTATIONS IN KCNJ13."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patient had nystagmus since childhood"
explanation: Nystagmus since childhood in a compound heterozygous patient.
- category: Ophthalmological
name: Nyctalopia
description: Night blindness reflecting early rod dysfunction.
phenotype_term:
preferred_term: Nyctalopia
term:
id: HP:0000662
label: Nyctalopia
evidence:
- reference: PMID:40294858
reference_title: "Clinical Characteristics of Patients With Less Common Causes of Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "nyctalopia was observed in KCNJ13 and OTX2"
explanation: Night blindness in the KCNJ13 patients of this series.
- category: Ophthalmological
name: Abnormal full-field electroretinogram
description: >-
Full-field ERG shows severe rod and cone dysfunction, ranging from
subnormal to unrecordable responses.
phenotype_term:
preferred_term: Severely reduced rod and cone full-field electroretinogram
term:
id: HP:0030466
label: Abnormal full-field electroretinogram
diagnostic: true
evidence:
- reference: PMID:25475713
reference_title: "A distinct vitreo-retinal dystrophy with early-onset cataract from recessive KCNJ13 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "electroretinography revealed severe cone-rod dysfunction, with only subnormal scotopic tracings recordable in both eyes"
explanation: >-
ERG in a KCNJ13 patient shows severe cone and rod dysfunction. Responses
were subnormal rather than absent, so the general abnormal-ERG term is
used rather than an undetectable-ERG term.
- category: Ophthalmological
name: Nummular retinal pigmentation
description: >-
Dense clumped or nummular pigment at the RPE level, most prominent at the
posterior pole; the most characteristic fundus sign of the disease.
phenotype_term:
preferred_term: Clumped nummular pigment at the level of the RPE
term:
id: HP:0030505
label: Nummular pigmentation of the retina
diagnostic: true
evidence:
- reference: PMID:27203561
reference_title: "LEBER CONGENITAL AMAUROSIS WITH LARGE RETINAL PIGMENT CLUMPS CAUSED BY COMPOUND HETEROZYGOUS MUTATIONS IN KCNJ13."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There were clumpy pigment deposits mostly in macular area, causing an uneven line of retinal pigment epithelium on spectral domain optical coherence tomography."
explanation: Clumped pigment deposits in a KCNJ13 patient.
- reference: PMID:40294858
reference_title: "Clinical Characteristics of Patients With Less Common Causes of Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "peripheral retinal pigment deposits were also densest in KCNJ13, followed by OTX2"
explanation: >-
Pigment deposits were densest in KCNJ13 among the uncommon LCA genes
compared.
- category: Ophthalmological
name: Macular atrophy
description: Macular atrophy, present in every KCNJ13 patient in one series.
phenotype_term:
preferred_term: Macular atrophy
term:
id: HP:0007401
label: Macular atrophy
evidence:
- reference: PMID:40294858
reference_title: "Clinical Characteristics of Patients With Less Common Causes of Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Macular atrophy was present in all patients with KCNJ13 variants"
explanation: >-
Macular atrophy in all three KCNJ13 patients of the series. Three
patients is too few for a frequency band.
- category: Ophthalmological
name: Optic disc pallor
description: Optic disc pallor in established disease.
phenotype_term:
preferred_term: Optic disc pallor
term:
id: HP:0000543
label: Optic disc pallor
evidence:
- reference: PMID:31647904
reference_title: "Missense variants in the conserved transmembrane M2 protein domain of KCNJ13 associated with retinovascular changes in humans and zebrafish."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "with areas of nummular pigment at the level of the RPE, especially over the posterior pole, macular atrophy and optic disc pallor with retinal vessel attenuation"
explanation: Disc pallor is listed among the characteristic KCNJ13-LCA features.
- category: Ophthalmological
name: Attenuation of retinal blood vessels
description: Narrowed retinal vessels accompanying the degeneration.
phenotype_term:
preferred_term: Attenuation of retinal blood vessels
term:
id: HP:0007843
label: Attenuation of retinal blood vessels
evidence:
- reference: PMID:31647904
reference_title: "Missense variants in the conserved transmembrane M2 protein domain of KCNJ13 associated with retinovascular changes in humans and zebrafish."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "with areas of nummular pigment at the level of the RPE, especially over the posterior pole, macular atrophy and optic disc pallor with retinal vessel attenuation"
explanation: Vessel attenuation is part of the characteristic fundus.
- category: Ophthalmological
name: Juvenile cataract
description: >-
Cataract in childhood or early adulthood, often needing extraction. It may
depend on genotype; it was prominent in homozygous p.Ile120Thr patients.
phenotype_term:
preferred_term: Juvenile or early-adult-onset cataract
term:
id: HP:0001118
label: Juvenile cataract
evidence:
- reference: PMID:25475713
reference_title: "A distinct vitreo-retinal dystrophy with early-onset cataract from recessive KCNJ13 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Juvenile or early-adult-onset cataract in the setting of a congenital vitreo-retinal dystrophy notable for fibrosis over the disc and clumped pigmentation in the posterior pole is a unique phenotype that suggests recessive KCNJ13 mutations."
explanation: Early cataract is part of the recessive KCNJ13 phenotype.
- reference: PMID:27203561
reference_title: "LEBER CONGENITAL AMAUROSIS WITH LARGE RETINAL PIGMENT CLUMPS CAUSED BY COMPOUND HETEROZYGOUS MUTATIONS IN KCNJ13."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "had cataracts extracted in both eyes"
explanation: Bilateral cataract extraction in a 31-year-old patient.
- category: Ophthalmological
name: Fibrosis over the optic disc
description: >-
Fibrosis over the optic disc, reported in the two homozygous p.Ile120Thr
patients as part of a distinctive fundus with clumped posterior-pole
pigment. HPO has no term for fibrosis of the disc, so the parent
optic-disc term is bound and the finding is carried in preferred_term.
notes: >-
OLS searches of HP for "optic disc fibrosis", "fibrosis optic disc",
"epipapillary" and "preretinal fibrosis" returned nothing. "epiretinal
membrane" returned HP:0100014 Epiretinal membrane, a fibrocellular sheet
on the inner retinal surface; the source describes fibrosis over the disc
and does not call it an epiretinal membrane, so that term was not used.
phenotype_term:
preferred_term: Fibrosis over the optic disc
term:
id: HP:0012795
label: Abnormal optic disc morphology
evidence:
- reference: PMID:25475713
reference_title: "A distinct vitreo-retinal dystrophy with early-onset cataract from recessive KCNJ13 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Juvenile or early-adult-onset cataract in the setting of a congenital vitreo-retinal dystrophy notable for fibrosis over the disc and clumped pigmentation in the posterior pole is a unique phenotype that suggests recessive KCNJ13 mutations."
explanation: Fibrosis over the disc is part of the recessive KCNJ13 fundus.
- category: Ophthalmological
name: Hypoplasia of the fovea
description: Absent foveal pit on OCT in the p.Thr153Ile siblings.
phenotype_term:
preferred_term: Foveal hypoplasia
term:
id: HP:0007750
label: Hypoplasia of the fovea
evidence:
- reference: PMID:31647904
reference_title: "Missense variants in the conserved transmembrane M2 protein domain of KCNJ13 associated with retinovascular changes in humans and zebrafish."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "OCT imaging showed that the retinal layers lacked normal segmentation and there was no evidence of a foveal depression or pit"
explanation: >-
Absent foveal pit in an affected sibling. Reported in one family only.
- category: Ophthalmological
name: Retinal neovascularization
description: >-
Retinal neovascularization with diffuse vascular leakage and preretinal
fibrosis developed at about age 17 in two siblings homozygous for the
M2-domain allele p.Thr153Ile. It was absent in younger siblings with the
same genotype and has not been reported with other alleles. How Kir7.1 loss
leads to vascular proliferation is unknown, so no mechanism node points to
this phenotype.
phenotype_term:
preferred_term: Retinal neovascularization
term:
id: HP:0030666
label: Retinal neovascularization
onset:
onset_category: JUVENILE
evidence:
- reference: PMID:31647904
reference_title: "Missense variants in the conserved transmembrane M2 protein domain of KCNJ13 associated with retinovascular changes in humans and zebrafish."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe a novel fibrovascular proliferation in the retina of two affected members of a KCNJ13-related LCA family with a homozygous c.458C > T, p.(Thr153Ile) missense mutation."
explanation: Fibrovascular proliferation in two p.Thr153Ile siblings.
sequelae:
- target: Vitreous hemorrhage
description: Neovascularization led to vitreous hemorrhage.
evidence:
- reference: PMID:31647904
reference_title: "Missense variants in the conserved transmembrane M2 protein domain of KCNJ13 associated with retinovascular changes in humans and zebrafish."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The affected siblings in family A developed retinal neovascularization with diffuse severe leakage and vitreous haemorrhages at age 17"
explanation: Hemorrhage followed neovascularization in both siblings.
- category: Ophthalmological
name: Vitreous hemorrhage
description: Vitreous hemorrhage secondary to retinal neovascularization.
phenotype_term:
preferred_term: Vitreous hemorrhage
term:
id: HP:0007902
label: Vitreous hemorrhage
evidence:
- reference: PMID:31647904
reference_title: "Missense variants in the conserved transmembrane M2 protein domain of KCNJ13 associated with retinovascular changes in humans and zebrafish."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The affected siblings in family A developed retinal neovascularization with diffuse severe leakage and vitreous haemorrhages at age 17"
explanation: Vitreous hemorrhage in two siblings at age 17.
genetic:
- name: KCNJ13
gene_term:
preferred_term: KCNJ13
term:
id: hgnc:6259
label: KCNJ13
association: Causative
relationship_type: CAUSATIVE
variant_origin: GERMLINE
features: >-
KCNJ13 (2q37) encodes Kir7.1, a weakly rectifying potassium channel subunit
that forms tetramers in the apical RPE membrane. Recessive loss-of-function
alleles cause LCA16. Specific heterozygous alleles, such as p.Arg162Trp,
cause autosomal dominant snowflake vitreoretinal degeneration instead.
notes: >-
ClinGen rates KCNJ13 Definitive for autosomal recessive inherited retinal
dystrophy (MONDO:0019118), a broader concept than this entry, so the tier
is not copied here.
evidence:
- reference: PMID:21763485
reference_title: "Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A screen of a further 333 unrelated individuals with recessive retinal degeneration identified an additional proband, homozygous for a missense mutation, c.722T>C (p.Leu241Pro), in the same gene."
explanation: A second unrelated family with a homozygous KCNJ13 allele.
- reference: PMID:25921210
reference_title: "A Novel KCNJ13 Nonsense Mutation and Loss of Kir7.1 Channel Function Causes Leber Congenital Amaurosis (LCA16)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Herein, we report the identification of a novel nonsense mutation in the second exon of the KCNJ13 gene that leads to a premature stop codon in association with LCA16."
explanation: Independent family with a KCNJ13 nonsense allele.
variants:
- name: NM_002242.4:c.496C>T (p.Arg166Ter)
type: NONSENSE
clinical_significance: PATHOGENIC
description: Homozygous in the first reported family.
evidence:
- reference: PMID:21763485
reference_title: "Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A combination of homozygosity mapping and exome sequencing identifies a homozygous nonsense mutation, c.496C>T (p.Arg166X), in a gene, KCNJ13, encoding a potassium channel subunit Kir7.1."
explanation: Discovery of the allele in homozygous form.
- name: NM_002242.4:c.722T>C (p.Leu241Pro)
type: MISSENSE
clinical_significance: PATHOGENIC
description: Homozygous in a second unrelated proband.
evidence:
- reference: PMID:21763485
reference_title: "Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "homozygous for a missense mutation, c.722T>C (p.Leu241Pro), in the same gene"
explanation: Reports the homozygous missense allele.
- name: NM_002242.4:c.359T>C (p.Ile120Thr)
type: MISSENSE
description: >-
Homozygous in two unrelated Saudi patients with early cataract and fibrosis
over the disc. No clinical-significance call is recorded here.
evidence:
- reference: PMID:25475713
reference_title: "A distinct vitreo-retinal dystrophy with early-onset cataract from recessive KCNJ13 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Next-generation sequencing of retinal dystrophy genes revealed homozygosity for a novel missense mutation in KCNJ13"
explanation: Allele co-segregates with disease.
- name: NM_002242.4:c.458C>T (p.Thr153Ile)
type: MISSENSE
description: >-
M2-domain allele, homozygous in two families. The protein reaches the
membrane but has negligible potassium conductance. The older siblings of
one family developed retinal neovascularization.
evidence:
- reference: PMID:35584325
reference_title: "Kir7.1 disease mutant T153I within the inner pore affects K(+) conduction."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We showed that the T153I mutation yielded a full-length protein localized to the cell membrane."
explanation: The allele is not a trafficking defect.
- name: c.314G>T (p.Ser105Ile) and c.655C>T (p.Gln219Ter)
type: COMPOUND_HETEROZYGOUS
description: Compound heterozygous in a 31-year-old man with large pigment clumps.
evidence:
- reference: PMID:27203561
reference_title: "LEBER CONGENITAL AMAUROSIS WITH LARGE RETINAL PIGMENT CLUMPS CAUSED BY COMPOUND HETEROZYGOUS MUTATIONS IN KCNJ13."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient was compound heterozygous for new mutations in KCNJ13 which encodes the Kir 7.1 potassium channel, c.314G>T (p.Ser105Ile) in exon 2 and c.655C>T (p.Gln219*) in exon 3."
explanation: Reports the two alleles in trans.
- name: c.158G>A (p.Trp53Ter)
type: NONSENSE
description: >-
Homozygous allele used for patient-derived iPSC-RPE and for the base
editing and suppressor-tRNA studies.
evidence:
- reference: PMID:30686507
reference_title: "Gene Augmentation and Readthrough Rescue Channelopathy in an iPSC-RPE Model of Congenital Blindness."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We derived human induced pluripotent stem cell (hiPSC)-RPE cells from an individual carrying a homozygous c.158G>A (p.Trp53∗) pathogenic variant of KCNJ13."
explanation: Identifies the patient genotype.
differential_diagnoses:
- name: Snowflake vitreoretinal degeneration
disease_term:
preferred_term: snowflake vitreoretinal degeneration
term:
id: MONDO:0008663
label: snowflake vitreoretinal degeneration
distinguishing_features:
- Caused by specific heterozygous KCNJ13 alleles (autosomal dominant)
- Fibrillar vitreous degeneration and minute crystalline retinal deposits
- Retinal detachment, with much better visual acuity than LCA16
evidence:
- reference: PMID:18179896
reference_title: "Mutations in KCNJ13 cause autosomal-dominant snowflake vitreoretinal degeneration."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Diagnostic features of SVD include fibrillar degeneration of the vitreous humor, early-onset cataract, minute crystalline deposits in the neurosensory retina, and retinal detachment."
explanation: Defines the allelic dominant KCNJ13 disorder.
diagnosis:
- name: Molecular genetic testing
description: >-
Confirmation by finding two KCNJ13 variants in trans, usually on a
retinal dystrophy gene panel. The clumped posterior-pole pigment and early
cataract can point to KCNJ13 before testing.
diagnosis_term:
preferred_term: retinal dystrophy gene panel sequencing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:25475713
reference_title: "A distinct vitreo-retinal dystrophy with early-onset cataract from recessive KCNJ13 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Next-generation sequencing of retinal dystrophy genes revealed homozygosity for a novel missense mutation in KCNJ13"
explanation: A retinal dystrophy gene panel made the molecular diagnosis.
treatments:
- name: Cataract surgery
description: Extraction of juvenile or early-adult cataract.
action_category: THERAPEUTIC
therapeutic_modality: SURGERY
treatment_term:
preferred_term: cataract extraction
term:
id: NCIT:C15329
label: Surgical Procedure
target_phenotypes:
- preferred_term: Juvenile cataract
term:
id: HP:0001118
label: Juvenile cataract
evidence:
- reference: PMID:27203561
reference_title: "LEBER CONGENITAL AMAUROSIS WITH LARGE RETINAL PIGMENT CLUMPS CAUSED BY COMPOUND HETEROZYGOUS MUTATIONS IN KCNJ13."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "had cataracts extracted in both eyes"
explanation: Bilateral cataract extraction in a KCNJ13 patient.
- name: Laser photocoagulation for retinal neovascularization
description: >-
Pan-retinal photocoagulation, with intravitreal anti-VEGF injection in one
patient, was used for the neovascular complication in the p.Thr153Ile
siblings. The source reports treatment, not outcome.
action_category: THERAPEUTIC
therapeutic_modality: SURGERY
treatment_term:
preferred_term: pan-retinal photocoagulation
term:
id: NCIT:C217424
label: Laser Photocoagulation
target_phenotypes:
- preferred_term: Retinal neovascularization
term:
id: HP:0030666
label: Retinal neovascularization
evidence:
- reference: PMID:31647904
reference_title: "Missense variants in the conserved transmembrane M2 protein domain of KCNJ13 associated with retinovascular changes in humans and zebrafish."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "they received extensive pan-retinal photocoagulation (PRP) and two intravitreal injections of avastin"
explanation: Reports the treatment given; no efficacy is claimed.
- name: KCNJ13 gene augmentation (preclinical)
description: >-
Lentiviral KCNJ13 delivery restored Kir7.1 current and membrane potential
in patient iPSC-RPE. No human trial is registered.
action_category: THERAPEUTIC
therapeutic_modality: GENE_THERAPY
treatment_term:
preferred_term: gene augmentation therapy
term:
id: NCIT:C15238
label: Gene Therapy
target_mechanisms:
- target: Loss of Kir7.1 Potassium Conductance in the RPE
description: Restores the missing channel in the RPE.
evidence:
- reference: PMID:30686507
reference_title: "Gene Augmentation and Readthrough Rescue Channelopathy in an iPSC-RPE Model of Congenital Blindness."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Similarly, we rescued Kir7.1 channel function after lentiviral gene delivery to the hiPSC-RPE cells."
explanation: Gene augmentation rescues channel function in patient RPE.
- name: Base editing of KCNJ13 p.Trp53Ter (preclinical)
description: >-
Silica-nanocapsule delivery of adenine base editor ABE8e mRNA and guide RNA
corrected p.Trp53Ter in patient cells and preserved ERG responses in a
mouse model.
action_category: THERAPEUTIC
therapeutic_modality: GENE_EDITING
treatment_term:
preferred_term: adenine base editing
term:
id: NCIT:C15238
label: Gene Therapy
target_mechanisms:
- target: Biallelic KCNJ13 Loss-of-Function Variants
description: Corrects the nonsense allele at the DNA level.
evidence:
- reference: PMID:37561581
reference_title: "Nonviral base editing of KCNJ13 mutation preserves vision in a model of inherited retinal channelopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In the LCA16 mouse model (Kcnj13W53X/+ΔR), RPE cells targeted SNC delivery of ABE8e mRNA preserved normal vision, measured by full-field electroretinogram (ERG)."
explanation: Base editing preserves retinal function in vivo.
- reference: PMID:37561581
reference_title: "Nonviral base editing of KCNJ13 mutation preserves vision in a model of inherited retinal channelopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Editing in both patient fibroblasts (47%) and human induced pluripotent stem cell-derived RPE (LCA16-iPSC-RPE) (17%) showed minimal off-target editing."
explanation: Editing efficiency in patient-derived cells.
- name: Suppressor tRNA for nonsense alleles (preclinical)
description: >-
An anticodon-engineered tRNA delivered by helper-dependent adenovirus
reads through the p.Trp53Ter stop codon and restores full-length Kir7.1.
It restored retinal function in a p.Trp53Ter mouse model.
action_category: THERAPEUTIC
therapeutic_modality: GENE_THERAPY
treatment_term:
preferred_term: anticodon-engineered tRNA gene delivery
term:
id: NCIT:C15238
label: Gene Therapy
target_mechanisms:
- target: Loss of Kir7.1 Potassium Conductance in the RPE
description: Restores full-length channel from a nonsense allele.
evidence:
- reference: PMID:40672310
reference_title: "Preventing vision loss in a mouse model of Leber Congenital Amaurosis by engineered tRNA."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Furthermore, in a W53X mouse model of LCA16, HDAd delivery of tRNATrp.UAG resulted in durable restoration of vision as measured by retinography."
explanation: Suppressor tRNA rescues vision in vivo.
- name: Readthrough drug for nonsense alleles (preclinical)
description: >-
A small-molecule translational readthrough drug restored Kir7.1 current
in patient p.Trp53Ter iPSC-RPE. It has not been tested in vivo or in
patients.
action_category: THERAPEUTIC
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: translational readthrough pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_mechanisms:
- target: Loss of Kir7.1 Potassium Conductance in the RPE
description: Restores full-length channel from a nonsense allele.
evidence:
- reference: PMID:30686507
reference_title: "Gene Augmentation and Readthrough Rescue Channelopathy in an iPSC-RPE Model of Congenital Blindness."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "After readthrough drug treatment, the LCA16 hiPSC cells were hyperpolarized by 30 mV, and the Kir7.1 current was restored."
explanation: A readthrough drug restores current in patient RPE.
animal_models:
- name: Kcnj13 RPE-conditional knockout mouse
species: Mouse
genotype: Kcnj13 flox/flox; Best1-cre
publication: PMID:30009826
description: >-
RPE-specific deletion, used because constitutive Kcnj13-null mice die on
postnatal day 1.
modeled_mechanisms:
- target: Loss of RPE Support for Photoreceptor Survival
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >-
RPE-restricted loss of Kcnj13 causes progressive outer nuclear layer
thinning and reduced light responses.
limitations: >-
A null allele in mouse; human alleles include missense variants with
residual protein. Mouse retina has no macula, so the macular atrophy and
posterior-pole pigment clumping seen in patients cannot be modelled.
evidence:
- reference: PMID:30009826
reference_title: "Conditional loss of Kcnj13 in the retinal pigment epithelium causes photoreceptor degeneration."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Furthermore, our findings show that widespread loss of Kcnj13 in the RPE leads to severe and progressive thinning of the outer nuclear layer and a reduced response to light."
explanation: Photoreceptor degeneration after RPE-specific deletion.
- name: kcnj13 obelix zebrafish
species: Zebrafish
genotype: kcnj13 obelix td15 (c.502T>C, p.Phe168Leu)
publication: PMID:30846767
description: >-
ENU mutant with a non-conducting M2-domain missense allele and late-onset
retinal degeneration.
modeled_mechanisms:
- target: Impaired RPE Phagocytosis of Photoreceptor Outer Segments
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: Reduced phagosome clearance precedes degeneration.
limitations: >-
Degeneration begins only at 12 months, much later than the infantile
human disease, and zebrafish retina differs from human retina.
evidence:
- reference: PMID:30846767
reference_title: "Phagosomal and mitochondrial alterations in RPE may contribute to KCNJ13 retinopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Detailed phenotyping of obelixtd15 fish revealed a late onset retinal degeneration at 12 months."
explanation: Late-onset degeneration in the mutant.
experimental_models:
- name: Patient p.Trp53Ter iPSC-derived RPE
experimental_model_type: IPSC_DERIVED_MODEL
description: >-
RPE differentiated from iPSCs of a patient homozygous for p.Trp53Ter.
cell_types:
- preferred_term: retinal pigment epithelial cell
term:
id: CL:0002586
label: retinal pigment epithelial cell
publication: PMID:30686507
modeled_mechanisms:
- target: Loss of Kir7.1 Potassium Conductance in the RPE
relationship: RECAPITULATES
fidelity: HIGH
model_scale: CELLULAR
description: Patient RPE lacks a functional Kir7.1 current.
limitations: >-
A monolayer culture without photoreceptors, so it cannot show the
photoreceptor degeneration that follows.
evidence:
- reference: PMID:30686507
reference_title: "Gene Augmentation and Readthrough Rescue Channelopathy in an iPSC-RPE Model of Congenital Blindness."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We found that the LCA16 hiPSC-RPE cells had normal morphology but did not express a functional Kir7.1 channel and were unable to demonstrate normal physiology."
explanation: Patient RPE reproduces the channel defect.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: Leber Congenital Amaurosis 16 · 2026-10-15T07:48:56Z · View source
New entry for LCA16 (MONDO:0013613, KCNJ13). Source report: research/Leber_Congenital_Amaurosis_16-deep-research-perplexity.md (Perplexity sonar-deep-research, default reasoning effort). Its reference validation resolved 23/23 identifiers and 3/3 quotes; preflight-dr returned WARN only because the heuristic gene lexicon counted the acronym RPE (retinal pigment epithelium) as a gene, and the report was read and confirmed to be about KCNJ13 and OMIM 614186. Papers not cited by the report were added from a PubMed search for KCNJ13 with retinal terms: PMID:25475713, PMID:31647904, PMID:35584325, PMID:40672310, PMID:25666713, PMID:18179896 and the GeneReviews LCA/EOSRD overview PMID:30285347. The pathograph runs from biallelic KCNJ13 loss of function through loss of RPE Kir7.1 conductance to impaired outer-segment phagocytosis, RPE oxidative stress and loss of photoreceptor support. The conflicting mouse (RPE survives) and human iPSC-RPE (RPE dies) results are both curated, the mouse result as REFUTE on the RPE death node. ClinGen's Definitive tier is for MONDO:0019118, not this disease, so no gene_disease_validity is recorded. Retinal neovascularization is left without an upstream mechanism because none is established. Validated with just validate, count-verified-snippets (68/68), validate-terms, check-genereviews (TAGGED) and check-causal-targets.
As-of date: October 15, 2026
Target disease: Leber congenital amaurosis 16
MONDO: MONDO:0013613
Disease class: Mendelian, inherited retinal dystrophy
Evidence scope: Human case reports/small pedigrees, patient-derived iPSC-RPE models, engineered mouse models, and zebrafish models. Because LCA16 is exceptionally rare—apparently <1% of LCA/EOSRD—phenotype frequencies, penetrance estimates, epidemiology, and prognosis remain imprecise. [143][176]
LCA16 is a severe, usually congenital or infantile, autosomal-recessive retinal dystrophy caused by biallelic loss-of-function variants in KCNJ13. KCNJ13 encodes Kir7.1, a tetrameric inwardly rectifying potassium channel concentrated in the apical processes of retinal pigment epithelial (RPE) cells. Loss of Kir7.1 impairs RPE membrane potential and subretinal potassium homeostasis, compromises photoreceptor-outer-segment phagocytosis, and initiates secondary mitochondrial dysfunction, oxidative stress, RPE disorganization, and rod-and-cone photoreceptor degeneration. [25][24][69]
The recognizable phenotype includes profound early visual impairment, congenital/infantile nystagmus, nyctalopia, severely reduced or absent rod-and-cone ERGs, progressive central and peripheral field loss, macular/RPE atrophy, dense or nummular pigment clumps—often prominent at the posterior pole—and cataract in some genotypes. A subset with the M2-domain p.Thr153Ile variant developed retinal neovascularization, diffuse leakage, fibrosis, and vitreous hemorrhage in adolescence. [55][56][58]
There is no approved KCNJ13-directed treatment. Care is supportive. HUB-101, an AAV5–KCNJ13 gene-augmentation candidate, remained publicly listed as preclinical/IND-enabling as of September 2026, with no registered human trial identified. The strongest recent advance is a 2023 preclinical study in which silica-nanocapsule delivery of ABE8e corrected p.Trp53Ter in patient fibroblasts (47%) and iPSC-RPE (17%), restored Kir7.1 currents, and preserved ERG and OCT outcomes in an engineered mouse model. [33][244][256]
LCA16 is the KCNJ13-associated form of Leber congenital amaurosis: a severe, bilateral, early-onset retinal dystrophy characterized by profound visual impairment during the first year of life and markedly reduced or absent full-field electroretinographic responses. The disease primarily begins in RPE cells but secondarily causes degeneration of rods, cones, and downstream retinal circuitry. [3][13][66]
The discovery study identified homozygous KCNJ13 variants in three affected individuals and concluded that they had “a similar early onset of visual loss, suggesting both impaired retinal development and progressive retinal degeneration, involving both rod and cone pathways.” PMID: 21763485; published July 15, 2011 [58]
| Resource | Identifier/name | Scope and qualification |
|---|---|---|
| MONDO | MONDO:0013613 | Leber congenital amaurosis 16; defined as LCA caused by mutation in KCNJ13. [5] |
| OMIM phenotype | 614186 | Leber congenital amaurosis 16. [6] |
| OMIM gene | 603208 | KCNJ13. [9] |
| Orphanet | ORPHA:65 | Umbrella Leber congenital amaurosis entry, not a unique LCA16 subtype code. [13] |
| ICD-10 | H35.5 | Hereditary retinal dystrophy; umbrella mapping used by Orphanet for LCA. [186] |
| ICD-11 | 9B70 | Hereditary retinal dystrophies; umbrella mapping rather than an LCA16-specific code. [186] |
| MeSH | D057130 | Leber Congenital Amaurosis; no separate LCA16 descriptor located. [181] |
| MedGen | C3280062 / UID 481692 | Leber congenital amaurosis 16. [3][211] |
| Disease Ontology | DOID:0110118 | LCA16 cross-reference reported in integrated disease resources. [4] |
| Gene | HGNC:6259; NCBI Gene 3769; Ensembl ENSG00000115474 | KCNJ13. [106] |
| Protein | UniProt O60928 | Kir7.1/inward rectifier potassium channel 13. [107] |
Synonyms: LCA16; Leber congenital amaurosis type 16; KCNJ13 Leber congenital amaurosis; Leber congenital amaurosis caused by mutation in KCNJ13; KCNJ13-related recessive retinopathy. [5][221]
The evidence is predominantly:
The established cause is biallelic germline pathogenic or likely pathogenic KCNJ13 variants causing reduced or absent Kir7.1 function. The gene–disease relationship is considered definitive for autosomal-recessive KCNJ13-related retinal dystrophy. [28][221]
Pathogenic mechanisms include:
The p.Trp53Ter channel produced approximately a 30-mV depolarization and 85% reduction in inward current in transfected cells; co-expression with wild-type protein did not exert a strong dominant-negative effect, supporting recessive loss of function. PMID: 25921210; published May 20, 2015 [376][379]
| Factor class | Evidence for LCA16 |
|---|---|
| Biallelic pathogenic KCNJ13 variants | Necessary and sufficient in established nonsyndromic cases; principal risk factor. |
| Family history | Increases prior probability, although an affected child may be the first recognized case in a family. |
| Parental consanguinity/shared ancestry | Increases the probability that both parents carry the same rare allele; several original families were consanguineous or from geographically restricted populations. [9][58] |
| Sex | No sex-specific risk has been demonstrated; autosomal inheritance predicts broadly equal susceptibility. |
| Age | Age determines manifestation and stage, not acquisition: disease usually manifests in infancy and progresses chronically. |
| Environmental, infectious, toxic or occupational exposure | No exposure is known to cause LCA16 or materially determine penetrance. |
| Protective genetic variants/modifiers | None validated. Heterozygous carriers of recessive loss-of-function alleles were clinically normal in the original families. [58] |
| Protective diet/lifestyle | No intervention prevents the genetic disease. General retinal-health advice is supportive, not proven disease-modifying. |
No human gene–environment interaction has been established. Oxidative challenge is a plausible downstream stress amplifier, not an initiating environmental cause. In KCNJ13-knockout human iPSC-RPE, tert-butyl hydroperoxide caused disproportionately increased oxidized glutathione and cell death, indicating that Kir7.1-deficient RPE is unusually vulnerable to oxidative stress. Whether ordinary diet, light, smoking, pollution or occupational exposures alter the human phenotype is unknown. PMID: 36413373; published November 22, 2022 [228]
Because fewer than several dozen molecularly characterized patients have been described in detail, the frequencies below are qualitative and should not be interpreted as population estimates.
| Phenotype | Type and characteristics | Onset/course and observed frequency | Suggested HPO term | Functional/QoL impact |
|---|---|---|---|---|
| Severe bilateral visual impairment/blindness | Symptom/sign; acuity ranges from approximately 0.7 logMAR to no light perception in published cases | Congenital or before age 1; usually severe and progressive; defining/near-universal | HP:0000505 Visual impairment; HP:0001141 Severely reduced visual acuity | Major effects on mobility, reading, education, independence and employment |
| Nystagmus | Clinical sign, generally sensory | Infancy; common/defining in published LCA16 cases | HP:0000639 | Impairs fixation and acuity |
| Nyctalopia/poor dark adaptation | Symptom from rod dysfunction | Early childhood onward; common in reports | HP:0000662 | Difficulty navigating in dim light |
| Absent or profoundly reduced ERG | Electrophysiologic abnormality affecting scotopic and photopic responses | Early and usually persistent; defining | HP:0000512 Abnormal electroretinogram; consider HP term for absent rod-and-cone response | Objective evidence of severe global retinal dysfunction |
| Progressive visual-field constriction | Functional sign | Childhood/adulthood; progressive but variable | HP:0001123 Visual field defect; HP:0001133 Constriction of peripheral visual field | Mobility and orientation impairment |
| Macular/RPE atrophy | Structural sign on fundoscopy/OCT | May become conspicuous during childhood or after the first decade; very characteristic | HP:0007401 Macular atrophy; HP:0007722 RPE atrophy | Progressive central-vision loss |
| Dense, clumpy or nummular retinal pigmentation | Fundus sign at RPE level, often posterior-pole predominant | May be subtle early and increase with age; highly characteristic in reported cases | HP:0007703 Abnormal retinal pigmentation; HP:0001146 Pigmentary retinal degeneration | Marker of RPE disorganization and degeneration |
| Outer-retinal loss/disorganization | OCT/pathology sign | Progressive; reported repeatedly | HP:0000548 Cone-rod dystrophy or HP:0000510 Rod-cone dystrophy may be used only when clinically appropriate | Correlates with loss of useful vision |
| Optic-disc pallor | Fundus sign | Later-stage, reported in several families | HP:0000543 | Reflects advanced retinal/optic pathway dysfunction |
| Retinal-vessel attenuation | Fundus sign | Progressive; reported in several families | HP:0007843 | Marker of severe retinal degeneration |
| Cataract | Ocular complication | Juvenile to early adult onset; recurrent but genotype-dependent | HP:0000518 Cataract | Further reduces residual vision; surgically treatable |
| Myopia | Refractive abnormality | Childhood; reported in some patients | HP:0000545 Myopia | Correctable contributor to poor acuity |
| Strabismus | Ocular-motor sign | Infancy/early childhood in some patients | HP:0000486 Strabismus; HP:0000487 if congenital | Cosmetic, fixation and amblyopia implications |
| Retinal neovascularization/leakage | Vascular complication | Not universal; developed around age 17 in two p.Thr153Ile siblings | HP:0007856 Retinal neovascularization, if available locally | Risk of hemorrhage, fibrosis and further visual loss |
| Vitreous hemorrhage | Complication of neovascularization | Adolescence in a subset | HP:0011531 Vitreous hemorrhage | Acute additional visual loss; may require surgery |
| Cataract/neovascular glaucoma after intervention | Treatment/ocular complication | Reported in an intensively treated p.Thr153Ile patient | Corresponding cataract/glaucoma HPO terms | Additional morbidity |
The original p.Arg166Ter siblings had visual acuities of 2.0 logMAR bilaterally and 1.78/1.48 logMAR at ages 34 and 32; the p.Leu241Pro patient had 1.45 logMAR bilaterally, absent rod/cone ERGs at age 10, and severe field loss by age 33. PMID: 21763485 [58]
A 31-year-old compound heterozygote had childhood nystagmus, acuities of 20/400 and 20/200, bilateral cataract extraction, and striking macular pigment clumps with thickened/disorganized retina. PMID: 27203561; published 2017 [56][361]
No LCA16-specific validated QoL study was located. Across RP/LCA genotypes, patient interviews identify effects on vision-dependent activities of daily living, mobility and broader HRQoL. The ViSIO-PRO/ObsRO instruments assess visual symptoms, mobility, ADL and distal HRQoL; psychometric validation included 83 adult/adolescent patients and 22 caregivers of children. PMID: 36847938; published April 2023 [151][157]
| Attribute | Value |
|---|---|
| Gene | KCNJ13 |
| Full name | Potassium inwardly rectifying channel subfamily J member 13 |
| HGNC | HGNC:6259 |
| NCBI Gene | 3769 |
| Ensembl | ENSG00000115474 |
| OMIM gene | 603208 |
| Chromosome | 2q37.1 |
| Protein | Kir7.1; UniProt O60928 |
| Canonical structure | 360 amino acids; cytoplasmic N and C termini, two transmembrane domains, one pore/selectivity loop; functional homotetramer |
| Molecular function | Inward rectifier potassium channel activity, suggested GO:0005242 |
| Core process | Potassium ion transmembrane transport, GO:0071805; potassium ion transport, GO:0006813 |
| Principal compartment | Plasma membrane, GO:0005886; apical plasma membrane, GO:0016324; ion-channel complex, GO:0034702 |
Kir7.1 has low conductance, weak inward rectification, unusual external-potassium dependence, and preferential Rb⁺ permeability; its RPE localization adjacent to Na⁺/K⁺-ATPase supports potassium recycling and subretinal ion homeostasis. [109][320][323]
The following table lists well-supported published biallelic variants, not every ClinVar submission or VUS.
| Variant, NM_002242.4 | Type/domain | Published zygosity and phenotype | Functional/classification evidence | Population data |
|---|---|---|---|---|
| c.158G>A, p.(Trp53Ter) | Nonsense, N-terminal cytoplasmic | Homozygous LCA16 | ClinVar pathogenic; truncation/mislocalization, approximately 85% current reduction; corrected by readthrough and base editing. [121][376] | Rare; exact current gnomAD AF not established here |
| c.314G>T, p.(Ser105Ile) | Missense | Compound heterozygous with p.Gln219Ter; LCA with pigment clumps | Reported disease-causing; absent from databases in original report | Absent from databases at publication |
| c.359T>C, p.(Ile120Thr) | Missense near pore/selectivity region | Homozygous in two unrelated Saudi patients with congenital vitreoretinal dystrophy and early cataract | Disease-causing/ClinVar record; channel reported to reach membrane but be inactive | Very rare; exact AF unavailable |
| c.431T>C, p.(Leu144Pro) | Missense, M2 | Homozygous severe early-onset retinal dystrophy in UAE families | Likely pathogenic based on segregation, extreme rarity and functional evidence; 2026 validation confirmed impaired current | 2 heterozygotes among 125,455 individuals; AF ≈0.0007971%. [84][135] |
| c.458C>T, p.(Thr153Ile) | Missense, M2 | Homozygous in two families; LCA with adolescent retinal neovascularization in older siblings | Damaging predictions; M2 inner-pore functional impairment; reported pathogenic/likely pathogenic | Rare; exact AF unavailable |
| c.496C>T, p.(Arg166Ter) | Nonsense | Homozygous in Middle Eastern siblings | Pathogenic; predicted loss of almost entire C-terminal intracellular segment; ClinVar pathogenic | gnomAD AF 1.30×10⁻⁵ in one 2025 WES report. [173] |
| c.655C>T, p.(Gln219Ter) | Nonsense | Compound heterozygous with p.Ser105Ile | Truncating, absent from databases in original report; disease-causing | Absent from databases at publication |
| c.722T>C, p.(Leu241Pro) | Missense, C-terminal β-sheet | Homozygous LCA16 | Pathogenic; predicted major conformational disruption; absent from controls in discovery report | Absent from 382 control chromosomes and contemporaneous databases |
| c.859T>C, p.(Ser287Pro) | Missense | Homozygous in later diagnostic cohorts | Reported likely pathogenic using PM2_supporting, PP1_moderate and PP3_strong | Rare; exact AF unavailable [225] |
The variants are germline, not somatic. Large structural variants, aneuploidies, repeat expansions and mitochondrial-DNA variants are not established causes of LCA16.
Heterozygous p.Arg162Trp and some other alleles cause autosomal-dominant snowflake vitreoretinal degeneration, not LCA16. Thus, variant-level mechanism matters: recessive loss-of-function alleles cause LCA16, whereas specific dominant alleles likely alter channel behavior through gain-of-function or dominant effects. [58][292]
No toxin, infection, radiation, nutritional deficiency, smoking, alcohol use or occupational exposure is known to cause LCA16. It is a monogenic inherited disorder.
Lifestyle recommendations—balanced diet, appropriate lighting, UV protection and avoidance of repeated eye pressing—are supportive and should not be represented as etiologic or proven disease-modifying interventions. [407][412]
No bacterial, viral, fungal or parasitic trigger has been identified; vaccination and antimicrobial prophylaxis are not disease-specific interventions.
In normal RPE, extracellular K⁺ falls from about 5 mM to 2 mM following photoreceptor light activation. Kir7.1 conductance increases as extracellular K⁺ falls, helping stabilize the RPE membrane and subretinal ionic microenvironment. Patient p.Trp53Ter iPSC-RPE had a membrane potential of −30.6 ±3.7 mV versus −50.0 ±5.1 mV in controls and lacked the characteristic Rb⁺-sensitive Kir7.1 current. PMID: 30686507; published January 24, 2019 [24]
Suggested GO terms
Patient-derived p.Trp53Ter iPSC-RPE took up substantially fewer photoreceptor outer segments than controls—66.5 ±7.4 versus 169 ±40 after short-term feeding—and processed fewer after prolonged digestion, 80.2 ±11.1 versus 244.2 ±27.6 per sampled field. CRISPR-knockout hiPSC-RPE also showed defective cell alignment and phagocytosis. PMID: 30686507PMID: 32437550 [17][24]
Suggested GO terms: GO:0006909 phagocytosis; GO:0038096 Fc-receptor-independent phagocytosis where appropriate; GO:0045494 photoreceptor-cell maintenance; GO:0007043 cell–cell junction assembly.
In kcnj13 p.Phe168Leu zebrafish, RPE phagosomes accumulated before visible retinal degeneration. At six months, mitochondria were increased 5.5-fold and ATP was reduced 26.2%; at 12 months, mitochondria were increased 6.4-fold, ATP remained reduced, and extensive retinal thinning and degeneration were present. The authors concluded:
“We propose that the retinal disease in this model is primarily a failure of phagosome physiology with a secondary mitochondrial dysfunction.”
PMID: 30846767; published March 7, 2019 [69]
Suggested GO terms: GO:0007005 mitochondrial organization; GO:0046034 ATP metabolic process; GO:0006091 generation of precursor metabolites and energy; GO:0006979 response to oxidative stress.
KCNJ13-knockout human RPE showed:
These results support increased oxidative stress and reduced oxidative-stress tolerance, although the exact link from K⁺ accumulation to mitochondrial ROS remains inferred. PMID: 36413373 [74]
Suggested terms: GO:0006979 response to oxidative stress; GO:0008219 cell death; GO:0097300 programmed necrotic cell death; GO:0006915 apoptotic process, where demonstrated.
LCA16 is not autoimmune or primarily inflammatory. Reactive Müller-cell GFAP expression in zebrafish indicates secondary retinal stress/gliosis. No consistent systemic immune abnormality is reported. Microglial or inflammatory activation may accompany degeneration but has not been established as an upstream cause.
| Technology | Evidence status |
|---|---|
| Bulk transcript/qPCR | Altered oxidative-stress genes, mitochondrial genes and stress markers in knockout RPE/zebrafish |
| Proteomics | No disease-specific large-scale human proteomic signature identified |
| Metabolomics/lipidomics | No validated patient diagnostic signature; ATP/glutathione changes shown experimentally |
| Single-cell RNA sequencing | No definitive LCA16 patient-retina single-cell atlas found |
| Spatial transcriptomics | No LCA16-specific study found |
| Multi-omics | No validated integrated human LCA16 analysis found |
| CRISPR functional genomics | CRISPR knockout iPSC-RPE, mosaic/conditional mice and mutation-specific base editing have been used |
| iPSC disease modeling | Strong evidence: patient-specific and engineered hiPSC-RPE reproduce electrophysiologic and phagocytic defects |
Cell Ontology suggestions: CL:0002586 retinal pigment epithelial cell; CL:0000210 photoreceptor cell; rod photoreceptor cell, cone photoreceptor cell, Müller glial cell and retinal bipolar neuron terms should be mapped to the current CL release.
| Level | Structures/cells | Ontology suggestions |
|---|---|---|
| Primary organ | Eye, bilaterally | UBERON:0000970 eye |
| Primary tissue | Retina | UBERON:0000966 |
| Initiating tissue | Retinal pigment epithelium/pigment epithelium of eye | UBERON:0007625; CL:0002586 |
| Secondary tissue | Neural retina | UBERON:0003902 |
| Principal secondary cells | Rod and cone photoreceptors | CL photoreceptor subclasses |
| Later secondary cells | Bipolar neurons and Müller glia/reactive retinal glia | Current CL bipolar-neuron and Müller-glial terms |
| Retinal layers | Photoreceptor outer segments, outer nuclear layer, outer plexiform layer; later inner nuclear layer | UBERON retinal-layer terms; parent UBERON:0001781 |
| Macula/posterior pole | Frequent site of dense pigmentation and atrophy | UBERON macula term where supported |
| Optic disc and vessels | Pallor and vascular attenuation; neovascularization in a subset | UBERON optic-disc and retinal-blood-vessel terms |
| Subcellular sites | Apical plasma membrane, ion-channel complex, phagosomes, mitochondria, cell junctions | GO:0016324, GO:0034702, GO:0031410, GO:0005739 |
Disease is bilateral. Marked unilateral asymmetry can occur in complications, such as unilateral vitreous hemorrhage or no-light-perception vision, but the inherited retinal dystrophy itself affects both eyes.
No consistent kidney, brain, endocrine or other systemic phenotype is established in recessive LCA16 despite Kir7.1 expression outside the eye.
| Stage | Typical findings |
|---|---|
| Congenital/infantile | Poor vision, nystagmus, strabismus or poor fixation; severely reduced ERG |
| Early childhood | Nyctalopia, severe acuity impairment; fundus may initially be less striking than functional loss |
| Later childhood/first decade | Increasing RPE pigmentation, macular atrophy, vessel attenuation and outer-retinal disorganization |
| Adolescence | Continued visual-field/acuity loss; cataract in susceptible genotypes; possible retinal leakage/neovascularization with p.Thr153Ile |
| Adulthood | Dense pigmentary maculopathy, severe central/peripheral loss, cataract or prior cataract surgery; some individuals retain limited residual vision |
The course is chronic and lifelong, usually progressive but variable. The p.Leu241Pro proband reported only mild progression between childhood and age 33, whereas other patients progressed to counting-fingers or no-light-perception vision. [58]
There is no spontaneous remission. Cataract extraction or treatment of neovascular complications may improve or preserve the non-retinal component of vision but does not reverse the underlying dystrophy.
Critical therapeutic window: biologically, treatment is most likely to help while RPE and photoreceptors remain structurally viable. This is inferred from retinal gene-therapy principles and animal rescue, not yet demonstrated clinically in LCA16.
LCA overall occurs in approximately 1 in 30,000–81,000 births, or roughly 1.2–3.3 per 100,000, accounts for about 5% of inherited retinal dystrophies, and has historically contributed substantially to childhood blindness. [136][138]
LCA16-specific prevalence and incidence are unknown. Current clinical summaries place KCNJ13 at <1% of all LCA/EOSRD, implying an extremely low prevalence, likely far below 1 per 100,000. [143][176]
No reliable sex ratio, carrier frequency, or annual incidence has been calculated. Cases have been reported in Middle Eastern/Jordanian, Saudi Arabian, European, French and Emirati families, demonstrating worldwide potential rather than geographic restriction. Consanguinity can elevate local prevalence. [58][84][392]
There is no routine blood chemistry, enzyme assay or circulating biomarker diagnostic for LCA16.
| Test | Utility |
|---|---|
| Inherited retinal-dystrophy/LCA multigene panel including KCNJ13 | Preferred initial molecular test because clinical overlap among LCA genes is extensive; should include copy-number analysis where possible |
| Exome sequencing | Appropriate if panel is negative, phenotype is atypical, or a broader syndromic differential remains |
| Genome sequencing | Useful after negative panel/exome for deep-intronic, regulatory or structural variants; specific incremental yield for LCA16 is unknown |
| Single-gene KCNJ13 sequencing | Reasonable when the dense pigment-clump phenotype is highly suggestive or for familial variant testing; GTR lists complete coding-region Sanger testing. [211] |
| Segregation testing | Confirm variants are in trans and identify carriers |
| Chromosomal microarray | Not first-line for classic isolated LCA16; consider with developmental anomalies or suspected CNV |
| Karyotype/FISH | Not routinely indicated |
| mtDNA testing | Not routinely indicated for classic LCA16 |
| Repeat-expansion testing | Not indicated |
| RNA sequencing | Research/second-line tool for suspected splice or deep-intronic variants; not a standard LCA16 diagnostic |
| Prenatal/PGT testing | Available once familial pathogenic variants are known |
The GTR LCA panel includes KCNJ13 along with other LCA genes. [212]
| Differential | Distinguishing points |
|---|---|
| Other nonsyndromic LCA/EOSRD genes—GUCY2D, CEP290, CRB1, RPE65, AIPL1, RDH12, LCA5, RPGRIP1, etc. | Molecular testing required; fundus/OCT patterns may guide but are not definitive |
| Achromatopsia | Cone ERG absent but rod responses preserved; photophobia and color-vision defect predominate |
| Congenital stationary night blindness | Nonprogressive; characteristic electronegative ERG with preserved a-wave in common forms |
| Oculocutaneous/ocular albinism | Hypopigmentation, foveal hypoplasia, usually normal full-field ERG and chiasmal misrouting |
| RPE65-related LCA | May show early nyctalopia with comparatively preserved central structure and is eligible for voretigene if biallelic RPE65, not KCNJ13 |
| Joubert/Senior-Løken/Alström syndromes | Neurologic, renal, metabolic or hearing manifestations |
| Infantile neuronal ceroid lipofuscinosis/peroxisomal disease | Progressive neurologic or systemic disease |
| Snowflake vitreoretinal degeneration | Usually autosomal dominant KCNJ13 allele; vitreous degeneration, snowflake deposits and comparatively preserved vision rather than congenital profound blindness |
Orphanet lists retinitis pigmentosa, Alström, Joubert, Stargardt, Senior-Løken and infantile neuronal ceroid lipofuscinosis among important differentials. [203]
LCA16 is not included in standard biochemical newborn screening. Appropriate targeted screening includes:
No LCA16-specific mortality, five-year survival or life-expectancy study exists. Available evidence describes an isolated ocular disorder; deaths directly attributable to LCA16 have not been reported.
Visual prognosis is poor:
The principal disability involves mobility, reading, face recognition, education, employment and independent daily activities. Early educational, orientation/mobility and assistive-technology services can mitigate developmental and QoL consequences, but do not restore retinal function. [151][153]
Potential prognostic factors, not yet validated in formal models, include:
No validated circulating or molecular prognostic biomarker exists.
| Intervention | Role | Suggested NCIt concept |
|---|---|---|
| Refraction and corrective lenses | Maximizes residual acuity | Corrective Lens Therapy |
| Low-vision rehabilitation, magnification and electronic aids | Improves reading/ADLs | Low Vision Rehabilitation |
| Orientation and mobility training | Improves safe navigation and independence | Occupational Therapy; Rehabilitation Therapy |
| Educational accommodations/Braille/assistive technology | Supports development and education | Supportive Care |
| Cataract surgery | Treats visually significant lens opacity where retinal potential remains | Cataract Surgery |
| Anti-VEGF, panretinal photocoagulation or vitrectomy | Case-specific management of neovascularization, leakage or vitreous hemorrhage | Antiangiogenic Therapy; Laser Photocoagulation; Vitrectomy |
| Amblyopia management | Appropriate in young children with asymmetric visual input | Amblyopia Therapy |
| Regular retinal surveillance | Detects progression and treatable complications | Ophthalmologic Examination |
GeneReviews recommends yearly acuity, refraction, slit-lamp examination, ophthalmoscopy and OCT, with visual-field/fundus imaging where feasible and ERG approximately every three to five years. [407][409]
There is no evidence-based LCA16-specific pharmacotherapy or pharmacogenomic prescribing guideline.
Voretigene neparvovec-rzyl (Luxturna) is FDA-approved only for confirmed biallelic RPE65-associated retinal dystrophy with viable retinal cells. It is not a treatment for KCNJ13-LCA16. [421][422]
| Strategy | Evidence and outcome | Development status |
|---|---|---|
| NB84 translational readthrough | In p.Trp53Ter patient iPSC-RPE, restored full-length protein, hyperpolarized cells by approximately 26–30 mV and restored Rb⁺-sensitive Kir7.1 currents | In vitro proof of concept; not approved [PMID:30686507] |
| Lentiviral KCNJ13 augmentation | Restored apical Kir7.1, membrane potential and current in patient iPSC-RPE; approximately 25% normal expression may be sufficient for substantial rescue | In vitro proof of concept |
| HUB-101 AAV5 gene augmentation | AAV5 carrying KCNJ13 under an RPE-directed VMD2 promoter; dose-dependent RPE transduction reported preclinically | Preclinical/IND-enabling; FDA orphan and rare-pediatric-disease designations reported; no NCT identified as of September 2026. [254][256] |
| ABE8e base editing of p.Trp53Ter | 47% correction in patient fibroblasts, 17% in iPSC-RPE, restored current; up to 16.8% in mouse RPE with ERG/OCT preservation | Preclinical, mutation-specific [PMID:37561581] |
| Suppressor tRNA/readthrough approaches | Small-molecule readthrough, nonsense-mediated-decay inhibition and suppressor tRNAs restored aspects of channel function in experimental systems | Preclinical |
| RPE cell replacement | Conceptually attractive for advanced RPE loss but no LCA16-specific human efficacy evidence | Experimental/not registered for LCA16 |
| Antioxidant/metabolic therapy | Mechanistically plausible from cellular/zebrafish studies but no human efficacy data | Exploratory |
Key 2023 abstract quotation:
“Editing in both patient fibroblasts (47%) and human induced pluripotent stem cell–derived RPE (LCA16-iPSC-RPE) (17%) showed minimal off-target editing. We detected functional Kir7.1 channels in the edited LCA16-iPSC-RPE.”
PMID: 37561581; published October 2, 2023 [33]
The 2023 base-editing study was encouraging but not equivalent to clinical safety: it used patient cells and an engineered mouse model, detected low-frequency bystander changes/indels, and could not use viable homozygous mice because complete biallelic loss was neonatal-lethal. [290]
The disease cannot be prevented by vaccination, diet or exposure avoidance. Reproductive options following molecular diagnosis include:
No disease-specific vaccine, antimicrobial prophylaxis or preventive medication exists.
| Species | Taxon/gene resource | Evidence |
|---|---|---|
| Human, Homo sapiens | NCBI Taxon 9606; KCNJ13 Gene 3769 | Natural LCA16 and dominant snowflake vitreoretinal degeneration |
| Mouse, Mus musculus | Taxon 10090; Kcnj13 Gene 100040591; MGI:3781032 | Engineered knockout, conditional knockout, mosaic and p.Trp53Ter models |
| Zebrafish, Danio rerio | Taxon 7955; kcnj13 Gene 555691; ZFIN ZDB-GENE-070129-1 | Naturally isolated/experimental obelix p.Phe168Leu mutant used as a retinal model |
| Rat, Rattus norvegicus | Taxon 10116; Kcnj13 Gene 94341 | Ortholog and physiologic studies; no established natural LCA16-equivalent disease |
Orthology is well conserved among human, mouse and zebrafish. [301][302][304]
No confirmed naturally occurring companion-animal breed disorder directly homologous to human KCNJ13-LCA16 was found in OMIA-oriented searches. Therefore:
| Model | Genotype/system | Phenotype recapitulated | Principal use and limitation |
|---|---|---|---|
| Patient-specific hiPSC-RPE | Homozygous p.Trp53Ter | Depolarization, absent Kir7.1 current, defective outer-segment phagocytosis; gross morphology initially preserved | Human genotype-specific mechanism and therapy testing; lacks whole-retina interactions |
| CRISPR KCNJ13-KO hiPSC-RPE | Frameshift/knockout | Cell misalignment, defective phagocytosis, oxidative vulnerability, death and protrusion | Dissects RPE-autonomous mechanisms; may not represent every missense allele |
| Heterologous CHO/HEK cells | Expressing mutant Kir7.1 | Channel current, localization, assembly and drug/editing rescue | High-throughput electrophysiology; not mature RPE |
| Mosaic CRISPR mouse | Patchy Kcnj13 loss in RPE | Local photoreceptor degeneration over mutant RPE; reduced light response | Demonstrates RPE cell autonomy; mosaic and not a natural germline phenotype |
| RPE-conditional mouse | Best1/VMD2-Cre Kcnj13 deletion | Progressive ONL loss, reduced/extinguished ERG, outer-plexiform and bipolar-cell changes | Strong tissue-specific model; timing and extent of Cre expression vary |
| Germline null mouse | Biallelic knockout | Embryonic or neonatal lethality depending on strain/model | Reveals extraocular developmental requirement but prevents straightforward adult retinal study |
| Kcnj13 p.Trp53Ter/+ΔR mouse | Knock-in plus RPE disruption of wild-type allele | Reduced ERG c-wave and progressive retinal dysfunction | Used for mutation-specific ABE8e rescue; engineered compound state differs from human homozygosity |
| Zebrafish obelix | Homozygous c.502T>C, p.Phe168Leu | Phagosome accumulation, enlarged mitochondria, reduced ATP, retinal thinning and visual decline | Defines temporal mechanism and vasculature; degeneration is late-onset rather than congenital |
| Retinal organoid/spatial models | No mature standardized LCA16 platform identified | — | Potential future tool for RPE–photoreceptor interaction |
In conditional mice, outer-nuclear-layer loss reached approximately 15% at postnatal day 15 and 70% by two months, with detectable structural loss preceding major visual dysfunction. PMID: 30009826; published July 25, 2018 [271]
The mosaic model showed that RPE cells lacking Kir7.1 could survive while adjacent photoreceptors degenerated, and nearby wild-type RPE could locally preserve photoreceptors—strong evidence that the initiating lesion is RPE-autonomous. [274][275]
Model resources: MGI/IMSR/MMRRC for mouse alleles, ZFIN for obelix/kcnj13, and patient/CRISPR hiPSC-RPE repositories associated with the cited laboratories. MMRRC identifies mouse Kcnj13 as NCBI Gene 100040591 and MGI:3781032. [306]
The evidence supports a coherent therapeutic rationale: LCA16 is monogenic, RPE-centered, recessive, and appears amenable to partial restoration of wild-type Kir7.1. Gene augmentation is potentially variant-agnostic and therefore applicable to more patients; base editing offers precise correction but is variant-specific and must address bystander/off-target edits, delivery coverage and durability. The principal translational uncertainty is whether treatment can restore function once extensive macular and photoreceptor atrophy is established. Early molecular diagnosis and quantitative OCT mapping of residual viable retina will therefore be central to eventual trial design.
Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 23 |
| Resolved | 23 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 3 |
| Quoted claims found in source | 3 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 23 |
| On topic | 18 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 54 |
| Resolved | 49 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 2 |
| Unverifiable | 3 |
| Terms whose name was checked | 16 |
| Terms named correctly | 9 |
| Terms named as a different term | 6 |
| Terms whose name is worth a second look | 1 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0013613 (2 mentions) - the report calls it "MONDO"; MONDO calls it Leber congenital amaurosis 16DOID:0110118 (1 mention) - the report calls it "Disease Ontology"; DOID calls it Leber congenital amaurosis 16HP:0000639 (1 mention) - the report calls it "Infancy; common/defining in published LCA16 cases"; HP calls it NystagmusHP:0000662 (1 mention) - the report calls it "Early childhood onward; common in reports"; HP calls it NyctalopiaHP:0000543 (1 mention) - the report calls it "Later-stage"; HP calls it Optic disc pallorHP:0007843 (1 mention) - the report calls it "Progressive; reported in several families"; HP calls it Attenuation of retinal blood vesselsThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
HP:0001146 (obsolete Pigmentary retinal degeneration) (1 mention) - replaced by HP:0000580HP:0000487 (obsolete Congenital strabismus) (1 mention) - replaced by HP:0000486The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
GO:0034702 (3 mentions) - the report calls it "ion-channel complex"; GO calls it monoatomic ion channel complexTerms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.