Senior-Loken syndrome (SLSN) is a rare autosomal recessive oculo-renal ciliopathy defined by the association of nephronophthisis (a chronic tubulointerstitial cystic kidney disease that progresses to end-stage renal disease) with a retinitis pigmentosa-like retinal dystrophy. It is genetically heterogeneous: the causative genes — including NPHP1, IQCB1 (NPHP5), CEP290 (NPHP6), SDCCAG8, WDR19, and others — all encode proteins of the primary cilium, its basal body, or the transition zone. The shared molecular lesion is dysfunction of the ciliary transition zone in renal tubular monocilia and of the photoreceptor connecting cilium, which simultaneously produces the renal and retinal arms of the disease. SLSN therefore sits within the nephronophthisis-related ciliopathy spectrum and overlaps clinically and genetically with Joubert, Bardet-Biedl, and Leber congenital amaurosis phenotypes (notably through pleiotropic genes such as CEP290).
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Conditions with similar clinical presentations that must be differentiated from Senior-Loken Syndrome:
name: Senior-Loken Syndrome
creation_date: "2026-06-17T12:00:00Z"
category: Mendelian
description: >-
Senior-Loken syndrome (SLSN) is a rare autosomal recessive oculo-renal
ciliopathy defined by the association of nephronophthisis (a chronic
tubulointerstitial cystic kidney disease that progresses to end-stage renal
disease) with a retinitis pigmentosa-like retinal dystrophy. It is genetically
heterogeneous: the causative genes — including NPHP1, IQCB1 (NPHP5), CEP290
(NPHP6), SDCCAG8, WDR19, and others — all encode proteins of the primary
cilium, its basal body, or the transition zone. The shared molecular lesion is
dysfunction of the ciliary transition zone in renal tubular monocilia and of
the photoreceptor connecting cilium, which simultaneously produces the renal
and retinal arms of the disease. SLSN therefore sits within the
nephronophthisis-related ciliopathy spectrum and overlaps clinically and
genetically with Joubert, Bardet-Biedl, and Leber congenital amaurosis
phenotypes (notably through pleiotropic genes such as CEP290).
disease_term:
preferred_term: Senior-Loken syndrome
term:
id: MONDO:0017842
label: Senior-Loken syndrome
parents:
- Ciliopathies
has_subtypes:
- name: SLSN1
display_name: Senior-Loken syndrome 1 (NPHP1)
subtype_term:
preferred_term: Senior-Loken syndrome 1
term:
id: MONDO:0009962
label: Senior-Loken syndrome 1
description: >-
NPHP1-related Senior-Loken syndrome, caused by mutations (most often the
recurrent homozygous deletion) in NPHP1 encoding nephrocystin-1. NPHP1 is the
same gene whose loss causes isolated juvenile nephronophthisis; the
renal-retinal SLSN1 phenotype reflects additional involvement of the
photoreceptor connecting cilium.
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "NPHP1 | nephrocystin 1 | hgnc:7905 | Disease-causing germline mutation(s) in"
explanation: >-
Orphanet lists NPHP1 among the disease-causing genes of Senior-Loken
syndrome, corresponding to the SLSN1 leaf class MONDO:0009962.
genes:
- preferred_term: NPHP1
term:
id: hgnc:7905
label: NPHP1
- name: SLSN3
display_name: Senior-Loken syndrome 3 (NPHP3)
subtype_term:
preferred_term: Senior-Loken syndrome 3
term:
id: MONDO:0011755
label: senior-loken syndrome 3
description: >-
NPHP3-related Senior-Loken syndrome. NPHP3 encodes nephrocystin-3, a
component of the nephronophthisis protein network that interacts with
inversin at the ciliary Inv compartment. NPHP3 was originally defined as the
adolescent nephronophthisis locus on chromosome 3q, and the SLSN3 designation
denotes the renal-retinal form linked to that locus. The gene attribution
here rests on the literature rather than on MONDO: MONDO:0011755 carries
neither a textual definition naming a gene nor a causal-gene OWL axiom, and
the separate NPHP3 gene class MONDO:0011456 nephronophthisis 3 is filed under
nephronophthisis rather than under Senior-Loken syndrome. That
isolated-nephronophthisis concept is bound on the NPHP3-related row of
kb/disorders/Nephronophthisis.yaml; this row is the renal-retinal form.
evidence:
- reference: PMID:22819833
reference_title: "Senior-Løken syndrome: a syndromic form of retinal dystrophy associated with nephronophthisis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Linkage to the NPHP3 locus has been shown in families with Senior-Løken syndrome (Omran et al., 2002)."
explanation: >-
Attributes the renal-retinal Senior-Loken phenotype to the NPHP3 locus on
the basis of family linkage, which is the basis for the SLSN3 designation.
The review restates work it did not perform, hence REVIEW_SYNTHESIS.
- reference: PMID:12438707
reference_title: "Candidate gene analysis of KIAA0678 encoding a DnaJ-like protein for adolescent nephronophthisis and Senior-Løken syndrome type 3."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Recently a locus for Senior-Løken syndrome (SLSN3) has been localized on chromosome 3q21-->q22 containing the whole critical NPHP3 region."
explanation: >-
Establishes that the SLSN3 locus coincides with the critical NPHP3 region,
which is why the numbered SLSN3 class corresponds to the NPHP3 gene.
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "NPHP3 | nephrocystin 3 | hgnc:7907 | Disease-causing germline mutation(s) in"
explanation: >-
Orphanet lists NPHP3 among the disease-causing genes of Senior-Loken
syndrome.
genes:
- preferred_term: NPHP3
term:
id: hgnc:7907
label: NPHP3
- name: SLSN4
display_name: Senior-Loken syndrome 4 (NPHP4)
subtype_term:
preferred_term: Senior-Loken syndrome 4
term:
id: MONDO:0011756
label: Senior-Loken syndrome 4
description: >-
NPHP4-related Senior-Loken syndrome. NPHP4 encodes nephrocystin-4 (HGNC
alias name nephroretinin; HGNC also carries SLSN4 as an alias symbol for this
gene), which forms a complex with nephrocystin-1 at the ciliary transition
zone and interacts with RPGR and RPGRIP1, which has been proposed as the link
to retinal degeneration in NPHP4 patients. NPHP4 accounts for a small minority
of molecularly solved Senior-Loken syndrome. In the case series cited below,
patients carrying INVS, NPHP3 or NPHP4 variants developed nephropathy before
retinopathy, the reverse of the CEP290 and IQCB1 order; that finding is
reported for the three genes together rather than for NPHP4 alone.
evidence:
- reference: PMID:36990420
reference_title: "Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Variants in 5 genes were identified in 74 patients from 70 unrelated
families, including CEP290 (61.4%), IQCB1 (28.6%), NPHP1 (4.2%), NPHP4
(2.9%), and WDR19 (2.9%).
explanation: >-
Identifies NPHP4 as one of the five genes carrying biallelic variants in a
molecularly solved Senior-Loken syndrome case series, and quantifies its
share of that cohort.
- reference: PMID:36990420
reference_title: "Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with pathogenic variants in CEP290 or IQCB1 presented early with
retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants
first developed nephropathy.
explanation: >-
Source for this row's statement that the renal manifestation comes first.
The finding is reported for INVS, NPHP3 and NPHP4 together, so it supports
the three genes as a set rather than NPHP4 on its own.
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "NPHP4 | nephrocystin 4 | hgnc:19104 | Disease-causing germline mutation(s) in"
explanation: >-
Orphanet lists NPHP4 among the disease-causing genes of Senior-Loken
syndrome.
genes:
- preferred_term: NPHP4
term:
id: hgnc:19104
label: NPHP4
- name: SLSN5
display_name: Senior-Loken syndrome 5 (IQCB1/NPHP5)
subtype_term:
preferred_term: Senior-Loken syndrome 5
term:
id: MONDO:0012225
label: Senior-Loken syndrome 5
description: >-
IQCB1 (NPHP5)-related Senior-Loken syndrome. IQCB1 encodes nephrocystin-5, an
IQ-domain protein that interacts with RPGR and calmodulin at the photoreceptor
connecting cilium and renal primary cilium. IQCB1 was identified as the most
frequent cause of SLSN, and all reported individuals with IQCB1 mutations have
retinitis pigmentosa.
evidence:
- reference: PMID:15723066
reference_title: "Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we identify, by positional cloning, mutations in an evolutionarily
conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of
SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals
with IQCB1 mutations have retinitis pigmentosa
explanation: >-
Identifies IQCB1/NPHP5 as the most frequent cause of Senior-Loken syndrome
(SLSN5, MONDO:0012225), with fully penetrant retinitis pigmentosa.
genes:
- preferred_term: IQCB1
term:
id: hgnc:28949
label: IQCB1
- name: SLSN6
display_name: Senior-Loken syndrome 6 (CEP290/NPHP6)
subtype_term:
preferred_term: Senior-Loken syndrome 6
term:
id: MONDO:0012433
label: Senior-Loken syndrome 6
description: >-
CEP290 (NPHP6)-related Senior-Loken syndrome. CEP290 encodes a large
centrosomal/transition-zone protein; its allelic spectrum is strikingly
pleiotropic, also causing Leber congenital amaurosis, Joubert syndrome, and
Meckel syndrome, illustrating how the same ciliary gene can produce
predominantly renal, retinal, or syndromic ciliopathy phenotypes.
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "CEP290 | centrosomal protein 290 | hgnc:29021 | Disease-causing germline mutation(s) in"
explanation: >-
Orphanet lists CEP290 among the disease-causing genes of Senior-Loken
syndrome, corresponding to the SLSN6 leaf class MONDO:0012433.
- reference: PMID:16909394
reference_title: "Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CEP290 mutations therefore represent one of the most frequent causes of LCA
identified so far
explanation: >-
Documents the pleiotropy of CEP290, which also causes Leber congenital
amaurosis, relevant to the retinal arm and differential diagnosis of
CEP290-related Senior-Loken syndrome.
genes:
- preferred_term: CEP290
term:
id: hgnc:29021
label: CEP290
- name: SLSN7
display_name: Senior-Loken syndrome 7 (SDCCAG8)
subtype_term:
preferred_term: Senior-Loken syndrome 7
term:
id: MONDO:0013326
label: Senior-Loken syndrome 7
description: >-
SDCCAG8-related Senior-Loken syndrome. SDCCAG8 encodes a centrosomal protein
involved in ciliogenesis and Sonic hedgehog signaling; biallelic mutations
cause a retinal-renal ciliopathy that can extend to additional Bardet-Biedl-like
features.
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "SDCCAG8 | SHH signaling and ciliogenesis regulator SDCCAG8 | hgnc:10671 | Disease-causing germline mutation(s) in"
explanation: >-
Orphanet lists SDCCAG8 among the disease-causing genes of Senior-Loken
syndrome, corresponding to the SLSN7 leaf class MONDO:0013326.
genes:
- preferred_term: SDCCAG8
term:
id: hgnc:10671
label: SDCCAG8
- name: SLSN8
display_name: Senior-Loken syndrome 8 (WDR19)
subtype_term:
preferred_term: Senior-Loken syndrome 8
term:
id: MONDO:0014579
label: Senior-Loken syndrome 8
description: >-
WDR19-related Senior-Loken syndrome. WDR19 encodes an intraflagellar
transport-A (IFT-A) complex subunit; its mutations cause a spectrum of
ciliopathies that includes the renal-retinal Senior-Loken phenotype as well
as skeletal ciliopathies.
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "WDR19 | WD repeat domain 19 | hgnc:18340 | Disease-causing germline mutation(s) in"
explanation: >-
Orphanet lists WDR19 among the disease-causing genes of Senior-Loken
syndrome, corresponding to the SLSN8 leaf class MONDO:0014579.
genes:
- preferred_term: WDR19
term:
id: hgnc:18340
label: WDR19
- name: SLSN9
display_name: Senior-Loken syndrome 9 (TRAF3IP1/IFT54)
subtype_term:
preferred_term: Senior-Loken syndrome 9
term:
id: MONDO:0014712
label: Senior-Loken syndrome 9
description: >-
TRAF3IP1-related Senior-Loken syndrome. The gene encodes IFT54, a subunit of
the intraflagellar transport B complex that carries axonemal cargo into the
cilium; IFT54 docks at the ciliary transition fibres and transition zone,
where it co-localises with CEP164, and the reported mutations keep it out of
that compartment. The reported variants are hypomorphic and produce only
mild structural ciliary defects; IFT54 additionally restrains cytoplasmic
microtubule stability through MAP4, an extraciliary role that contributes to
the phenotype. HGNC renamed TRAF3IP1 to IFT54 on 2026-03-20; the identifier
hgnc:17861 is unchanged.
evidence:
- reference: PMID:26487268
reference_title: "Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor
Interacting Protein 1) in eight patients from five families with
nephronophthisis (NPH) and retinal degeneration, two of the most common
manifestations of ciliopathies.
explanation: >-
Original report of TRAF3IP1 variants in patients with the combination of
nephronophthisis and retinal degeneration that defines Senior-Loken
syndrome, the basis for the SLSN9 class.
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "TRAF3IP1 | TRAF3 interacting protein 1 | hgnc:17861 | Disease-causing germline mutation(s) (loss of function) in"
explanation: >-
Orphanet lists TRAF3IP1 among the disease-causing genes of Senior-Loken
syndrome, recording loss of function as the mechanism.
genes:
- preferred_term: TRAF3IP1
term:
id: hgnc:17861
label: TRAF3IP1
inheritance:
- name: Autosomal Recessive
description: >-
Senior-Loken syndrome is inherited in an autosomal recessive manner; affected
individuals carry biallelic (homozygous or compound heterozygous) mutations
in one of the causative ciliary genes.
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "A rare autosomal recessive oculo-renal ciliopathy characterized by the association of nephronophthisis (NPHP), a chronic kidney disease, with retinal dystrophy."
explanation: >-
Orphanet's definition establishes autosomal recessive inheritance of the
renal-retinal ciliopathy.
- reference: PMID:40427560
reference_title: "Senior-Loken Syndrome: Ocular Perspectives on Genetics, Pathogenesis, and Management."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Senior-Loken syndrome (SLSN) is a group of rare autosomal recessive
disorders caused by dysfunction of the primary cilium
explanation: >-
Confirms autosomal recessive inheritance and the primary-cilium basis of
the disorder. (Source is a narrative review; classified as OTHER.)
prevalence:
- population: Worldwide
measure_type: POINT_PREVALENCE
prevalence_class: BAND_1_9_PER_1000000
rate_low: 0.1
rate_high: 0.9
percentage: 1-9 per 1,000,000
notes: >-
Orphanet records a worldwide point prevalence of 1-9 per 1,000,000 for
Senior-Loken syndrome, consistent with its classification as a rare disorder.
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "1-9 / 1 000 000 | Worldwide | Point prevalence"
explanation: >-
Orphanet's epidemiology table gives the worldwide point prevalence of
Senior-Loken syndrome.
pathophysiology:
- name: Ciliary Transition Zone Dysfunction
conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
description: >-
The unifying upstream lesion of Senior-Loken syndrome is dysfunction of the
ciliary base. The nephrocystin proteins encoded by the SLSN genes localize to
the transition zone of renal and respiratory cilia and to the photoreceptor
connecting cilium, where they gate ciliary membrane composition and
bidirectional cargo transport. Loss of these proteins produces a structurally
present but functionally incompetent cilium that cannot correctly
compartmentalize signaling and phototransduction machinery, biasing the
downstream phenotype toward the renal tubule and the photoreceptor. The ten
genes bound here are not all transition-zone proteins in the strict sense:
they span the transition zone itself, the distal appendages that anchor it
(CEP164), and the intraflagellar transport machinery that moves cargo
through it (WDR19 in IFT-A, TRAF3IP1 in IFT-B). They are grouped at this one
node because each defect produces the same functional outcome - a
structurally present cilium that cannot gate its own membrane or cargo -
which is what the three biological processes recorded here describe.
biological_processes:
- preferred_term: cilium assembly
term:
id: GO:0060271
label: cilium assembly
modifier: ABNORMAL
- preferred_term: protein localization to cilium
term:
id: GO:0061512
label: protein localization to cilium
modifier: ABNORMAL
- preferred_term: intraflagellar transport
term:
id: GO:0042073
label: intraciliary transport
modifier: ABNORMAL
cellular_components:
- preferred_term: ciliary transition zone
term:
id: GO:0035869
label: ciliary transition zone
- preferred_term: primary cilium
term:
id: GO:0005929
label: cilium
cell_types:
- preferred_term: ciliated cell
term:
id: CL:0000064
label: ciliated cell
genes:
- preferred_term: NPHP1
term:
id: hgnc:7905
label: NPHP1
- preferred_term: IQCB1
term:
id: hgnc:28949
label: IQCB1
- preferred_term: CEP290
term:
id: hgnc:29021
label: CEP290
- preferred_term: SDCCAG8
term:
id: hgnc:10671
label: SDCCAG8
- preferred_term: WDR19
term:
id: hgnc:18340
label: WDR19
- preferred_term: NPHP3
term:
id: hgnc:7907
label: NPHP3
- preferred_term: NPHP4
term:
id: hgnc:19104
label: NPHP4
- preferred_term: INVS
term:
id: hgnc:17870
label: INVS
- preferred_term: CEP164
term:
id: hgnc:29182
label: CEP164
- preferred_term: TRAF3IP1
term:
id: hgnc:17861
label: TRAF3IP1
downstream:
- target: Renal Tubular Cystic and Fibrotic Disease
description: >-
Transition-zone dysfunction in renal tubular monocilia drives the
nephronophthisis arm of the disease.
- target: Photoreceptor Connecting Cilium Degeneration
description: >-
Connecting-cilium dysfunction impairs photoreceptor outer-segment
maintenance, driving the retinal-dystrophy arm of the disease.
- target: Global Developmental Delay
description: Pleiotropic transition-zone and centrosomal ciliopathy genes can extend the Senior-Loken phenotype to neurodevelopmental delay.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0001263 | Global developmental delay | Very frequent (99-80%)"
explanation: Orphanet records global developmental delay as a very frequent feature of Senior-Loken syndrome.
- target: Ataxia
description: Extended nephronophthisis-related ciliopathy phenotypes can include cerebellar/coordination involvement.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0001251 | Ataxia | Occasional (29-5%)"
explanation: Orphanet records ataxia as an occasional feature of Senior-Loken syndrome.
- target: Premature Ovarian Insufficiency
description: Senior-Loken syndrome can include reproductive involvement; the precise ciliary intermediate remains unresolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0008209 | Premature ovarian insufficiency | Frequent (79-30%)"
explanation: Orphanet records premature ovarian insufficiency as a frequent Senior-Loken syndrome feature.
evidence:
- reference: PMID:16885411
reference_title: "Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
nephrocystin specifically localizes at the ciliary base to the transition
zone of renal and respiratory cilia and to photoreceptor connecting cilia
explanation: >-
Localizes nephrocystin to the transition zone of renal cilia and the
photoreceptor connecting cilium, the shared cellular lesion of Senior-Loken
syndrome and the basis for conformance to the transition-zone module node.
- reference: PMID:15723066
reference_title: "Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
these proteins localize to connecting cilia of photoreceptors and to
primary cilia of renal epithelial cells
explanation: >-
Nephrocystin-5 (IQCB1) and its partners localize to both the photoreceptor
connecting cilium and renal primary cilium, linking the two affected
compartments to a common ciliary lesion.
- name: Renal Tubular Cystic and Fibrotic Disease
conforms_to: "ciliopathy_dysfunction#Renal Tubular Cystic and Fibrotic Disease"
description: >-
Renal tubular epithelial cells use the primary cilium as a flow and signaling
sensor that maintains tubular architecture. Ciliary dysfunction produces the
nephronophthisis phenotype: a chronic tubulointerstitial nephropathy with
corticomedullary cysts, tubular basement membrane disruption, and
interstitial fibrosis that progresses to end-stage renal disease, typically
in childhood or adolescence. Nephronophthisis is the leading genetic cause of
end-stage renal failure in children.
biological_processes:
- preferred_term: cilium assembly
term:
id: GO:0060271
label: cilium assembly
modifier: ABNORMAL
cell_types:
- preferred_term: kidney tubule epithelial cell
term:
id: CL:0002518
label: kidney epithelial cell
locations:
- preferred_term: kidney
term:
id: UBERON:0002113
label: kidney
evidence:
- reference: PMID:21071979
reference_title: "Mechanisms of nephronophthisis and related ciliopathies."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Nephronophthisis is a recessive disorder of the kidney that is the leading
cause of end-stage renal failure in children.
explanation: >-
Establishes nephronophthisis, the renal arm of Senior-Loken syndrome, as a
recessive ciliopathy and the leading genetic cause of pediatric end-stage
renal failure.
- reference: PMID:16885411
reference_title: "Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
nephrocystin deficiency or dysfunction at the transition zone of renal
monocilia and the photoreceptor connecting cilium might explain renal
failure and retinal degeneration that are observed in patients with NPHP1
explanation: >-
Directly links transition-zone dysfunction in renal monocilia to the renal
failure of nephronophthisis.
downstream:
- target: Nephronophthisis
description: Renal tubular ciliary dysfunction produces the nephronophthisis component of Senior-Loken syndrome.
causal_link_type: DIRECT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0000090 | Nephronophthisis | Frequent (79-30%)"
explanation: Orphanet records nephronophthisis as a frequent Senior-Loken syndrome feature.
- target: Tubulointerstitial Fibrosis
description: The nephronophthisis renal lesion includes interstitial fibrosis and tubular atrophy.
causal_link_type: DIRECT
evidence:
- reference: PMID:23559409
reference_title: "Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In renal histology, the most prominent features of NPHP are tubular atrophy, basement membrane disintegration, interstitial fibrosis, and cyst formation."
explanation: The large NPHP-RC cohort paper describes tubulointerstitial fibrosis as a prominent nephronophthisis histologic feature.
- target: Stage 5 Chronic Kidney Disease
description: Progressive nephronophthisis causes end-stage renal disease in childhood or adolescence.
causal_link_type: DIRECT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0003774 | Stage 5 chronic kidney disease | Very frequent (99-80%)"
explanation: Orphanet records stage 5 chronic kidney disease as very frequent in Senior-Loken syndrome.
- target: Hypertension
description: Progressive chronic kidney disease in Senior-Loken syndrome can lead to hypertension.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0000822 | Hypertension | Very frequent (99-80%)"
explanation: Orphanet records hypertension as a very frequent Senior-Loken syndrome feature.
- target: Short Stature
description: Pediatric chronic kidney disease contributes to growth impairment and short stature.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0004322 | Short stature | Very frequent (99-80%)"
explanation: Orphanet records short stature as a very frequent Senior-Loken syndrome feature.
- name: Photoreceptor Connecting Cilium Degeneration
conforms_to: "ciliopathy_dysfunction#Photoreceptor Connecting Cilium Degeneration"
description: >-
Photoreceptor outer segments are specialized non-motile sensory cilia
connected to the cell body by the connecting cilium, through which all
phototransduction cargo is trafficked. In Senior-Loken syndrome, nephrocystin
dysfunction at the connecting cilium impairs outer-segment morphogenesis and
maintenance, causing progressive photoreceptor death and a retinitis
pigmentosa-like retinal dystrophy. Retinal involvement is highly penetrant and
is the feature that distinguishes Senior-Loken syndrome from isolated
nephronophthisis.
biological_processes:
- preferred_term: photoreceptor cell maintenance
term:
id: GO:0045494
label: photoreceptor cell maintenance
modifier: DECREASED
cell_types:
- preferred_term: photoreceptor cell
term:
id: CL:0000210
label: photoreceptor cell
locations:
- preferred_term: retina
term:
id: UBERON:0000966
label: retina
evidence:
- reference: PMID:15723066
reference_title: "Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ten percent of affected individuals have retinitis pigmentosa, constituting
the renal-retinal Senior-Loken syndrome (SLSN).
explanation: >-
Defines the retinal arm (retinitis pigmentosa) that, combined with
nephronophthisis, constitutes Senior-Loken syndrome.
downstream:
- target: Retinal Dystrophy
description: Photoreceptor connecting-cilium dysfunction causes the retinitis-pigmentosa-like retinal dystrophy.
causal_link_type: DIRECT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0000556 | Retinal dystrophy | Very frequent (99-80%)"
explanation: Orphanet records retinal dystrophy as a very frequent Senior-Loken syndrome feature.
- target: Visual Impairment
description: Progressive photoreceptor degeneration results in visual impairment.
causal_link_type: DIRECT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0000505 | Visual impairment | Very frequent (99-80%)"
explanation: Orphanet records visual impairment as a very frequent feature.
- target: Progressive Visual Loss
description: Retinal dystrophy advances over time, producing progressive visual loss.
causal_link_type: DIRECT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0000529 | Progressive visual loss | Frequent (79-30%)"
explanation: Orphanet records progressive visual loss as a frequent feature.
- target: Abnormal Retinal Pigmentation
description: The retinitis-pigmentosa-like retinal dystrophy includes pigmentary retinal changes.
causal_link_type: DIRECT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0007703 | Abnormality of retinal pigmentation | Very frequent (99-80%)"
explanation: Orphanet records abnormal retinal pigmentation as a very frequent feature.
phenotypes:
- name: Nephronophthisis
category: Renal
description: >-
Nephronophthisis — a chronic tubulointerstitial cystic kidney disease — is
the obligate renal component of Senior-Loken syndrome.
phenotype_term:
preferred_term: Nephronophthisis
term:
id: HP:0000090
label: Nephronophthisis
frequency: FREQUENT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0000090 | Nephronophthisis | Frequent (79-30%)"
explanation: >-
Orphanet records nephronophthisis as a frequent feature of Senior-Loken
syndrome; frequency band Frequent (79-30%) maps to FREQUENT.
- name: Retinal Dystrophy
category: Ophthalmologic
description: >-
A retinitis pigmentosa-like retinal dystrophy is the defining ocular
component of Senior-Loken syndrome, reflecting photoreceptor connecting-cilium
dysfunction.
phenotype_term:
preferred_term: Retinal dystrophy
term:
id: HP:0000556
label: Retinal dystrophy
frequency: VERY_FREQUENT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0000556 | Retinal dystrophy | Very frequent (99-80%)"
explanation: >-
Orphanet records retinal dystrophy as a very frequent feature; frequency
band Very frequent (99-80%) maps to VERY_FREQUENT.
- name: Visual Impairment
category: Ophthalmologic
description: >-
Visual impairment results from progressive retinal degeneration and is a
near-universal feature of Senior-Loken syndrome.
phenotype_term:
preferred_term: Visual impairment
term:
id: HP:0000505
label: Visual impairment
frequency: VERY_FREQUENT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0000505 | Visual impairment | Very frequent (99-80%)"
explanation: >-
Orphanet records visual impairment as a very frequent feature; band Very
frequent (99-80%) maps to VERY_FREQUENT.
- name: Progressive Visual Loss
category: Ophthalmologic
description: >-
Vision typically declines progressively as the retinal dystrophy advances.
phenotype_term:
preferred_term: Progressive visual loss
term:
id: HP:0000529
label: Progressive visual loss
frequency: FREQUENT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0000529 | Progressive visual loss | Frequent (79-30%)"
explanation: >-
Orphanet records progressive visual loss as a frequent feature; band
Frequent (79-30%) maps to FREQUENT.
- name: Abnormal Retinal Pigmentation
category: Ophthalmologic
description: >-
Retinal pigmentary changes typical of a retinitis pigmentosa-like dystrophy
are seen on fundus examination.
phenotype_term:
preferred_term: Abnormal retinal pigmentation
term:
id: HP:0007703
label: Abnormal retinal pigmentation
frequency: VERY_FREQUENT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0007703 | Abnormality of retinal pigmentation | Very frequent (99-80%)"
explanation: >-
Orphanet records abnormal retinal pigmentation as a very frequent feature;
band Very frequent (99-80%) maps to VERY_FREQUENT.
- name: Stage 5 Chronic Kidney Disease
category: Renal
description: >-
Nephronophthisis in Senior-Loken syndrome progresses to stage 5 chronic
kidney disease (end-stage renal disease), typically in childhood or
adolescence, requiring renal replacement therapy.
phenotype_term:
preferred_term: Stage 5 chronic kidney disease
term:
id: HP:0003774
label: Stage 5 chronic kidney disease
frequency: VERY_FREQUENT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0003774 | Stage 5 chronic kidney disease | Very frequent (99-80%)"
explanation: >-
Orphanet records stage 5 chronic kidney disease as a very frequent feature;
band Very frequent (99-80%) maps to VERY_FREQUENT.
- name: Tubulointerstitial Fibrosis
category: Renal
description: >-
The nephronophthisis renal lesion includes tubular atrophy, basement
membrane disruption, interstitial fibrosis, and cyst formation.
phenotype_term:
preferred_term: Tubulointerstitial fibrosis
term:
id: HP:0005576
label: Tubulointerstitial fibrosis
evidence:
- reference: PMID:23559409
reference_title: "Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In renal histology, the most prominent features of NPHP are tubular atrophy, basement membrane disintegration, interstitial fibrosis, and cyst formation."
explanation: This large NPHP-RC cohort paper identifies interstitial fibrosis as a prominent histologic feature of nephronophthisis-related ciliopathies.
- name: Global Developmental Delay
category: Neurologic
description: >-
A subset of patients, particularly those with pleiotropic transition-zone
genes, show global developmental delay as part of an extended ciliopathy
phenotype.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
frequency: VERY_FREQUENT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0001263 | Global developmental delay | Very frequent (99-80%)"
explanation: >-
Orphanet records global developmental delay as a very frequent feature;
band Very frequent (99-80%) maps to VERY_FREQUENT.
- name: Ataxia
category: Neurologic
description: >-
Ataxia can occur in Senior-Loken syndrome, reflecting overlap with the
cerebellar involvement of related ciliopathies such as Joubert syndrome.
phenotype_term:
preferred_term: Ataxia
term:
id: HP:0001251
label: Ataxia
frequency: OCCASIONAL
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0001251 | Ataxia | Occasional (29-5%)"
explanation: >-
Orphanet records ataxia as an occasional feature; band Occasional (29-5%)
maps to OCCASIONAL.
- name: Hypertension
category: Cardiovascular
description: >-
Hypertension occurs as a frequent complication of chronic kidney disease in
Senior-Loken syndrome, reflecting the progressive renal impairment of
nephronophthisis.
phenotype_term:
preferred_term: Hypertension
term:
id: HP:0000822
label: Hypertension
frequency: VERY_FREQUENT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0000822 | Hypertension | Very frequent (99-80%)"
explanation: >-
Orphanet records hypertension as a very frequent feature; band Very
frequent (99-80%) maps to VERY_FREQUENT.
- name: Short Stature
category: Growth
description: >-
Short stature occurs in many children with Senior-Loken syndrome as a
consequence of pediatric chronic kidney disease and its associated growth
impairment.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
frequency: VERY_FREQUENT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0004322 | Short stature | Very frequent (99-80%)"
explanation: >-
Orphanet records short stature as a very frequent feature; band Very
frequent (99-80%) maps to VERY_FREQUENT.
- name: Premature Ovarian Insufficiency
category: Reproductive
description: >-
Premature ovarian insufficiency occurs as a frequent extrarenal, extra-ocular
manifestation in Senior-Loken syndrome, reflecting ciliary dysfunction in
ovarian follicle development.
phenotype_term:
preferred_term: Premature ovarian insufficiency
term:
id: HP:0008209
label: Premature ovarian insufficiency
frequency: FREQUENT
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "HP:0008209 | Premature ovarian insufficiency | Frequent (79-30%)"
explanation: >-
Orphanet records premature ovarian insufficiency as a frequent feature;
band Frequent (79-30%) maps to FREQUENT.
genetic:
- name: NPHP1
association: Causative
relationship_type: CAUSATIVE
subtype: SLSN1
gene_term:
preferred_term: NPHP1
term:
id: hgnc:7905
label: NPHP1
notes: >-
Biallelic NPHP1 mutations (commonly the recurrent homozygous deletion) cause
SLSN1; NPHP1 also causes isolated juvenile nephronophthisis.
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "NPHP1 | nephrocystin 1 | hgnc:7905 | Disease-causing germline mutation(s) in"
explanation: >-
Orphanet lists NPHP1 as a disease-causing gene of Senior-Loken syndrome.
- name: IQCB1
association: Causative
relationship_type: CAUSATIVE
subtype: SLSN5
gene_term:
preferred_term: IQCB1
term:
id: hgnc:28949
label: IQCB1
notes: >-
IQCB1 (NPHP5) encodes nephrocystin-5 and was identified as the most frequent
cause of Senior-Loken syndrome; all reported IQCB1 patients have retinitis
pigmentosa.
evidence:
- reference: PMID:15723066
reference_title: "Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we identify, by positional cloning, mutations in an evolutionarily
conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of
SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals
with IQCB1 mutations have retinitis pigmentosa
explanation: >-
Original identification of IQCB1/NPHP5 as the most frequent cause of
Senior-Loken syndrome, with fully penetrant retinitis pigmentosa.
- name: CEP290
association: Causative
relationship_type: CAUSATIVE
subtype: SLSN6
gene_term:
preferred_term: CEP290
term:
id: hgnc:29021
label: CEP290
notes: >-
CEP290 (NPHP6) encodes a transition-zone protein; its highly pleiotropic
allelic spectrum spans Senior-Loken syndrome, Leber congenital amaurosis,
Joubert syndrome, and Meckel syndrome.
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "CEP290 | centrosomal protein 290 | hgnc:29021 | Disease-causing germline mutation(s) in"
explanation: >-
Orphanet lists CEP290 as a disease-causing gene of Senior-Loken syndrome.
- name: SDCCAG8
association: Causative
relationship_type: CAUSATIVE
subtype: SLSN7
gene_term:
preferred_term: SDCCAG8
term:
id: hgnc:10671
label: SDCCAG8
notes: >-
SDCCAG8 encodes a centrosomal protein involved in ciliogenesis and Sonic
hedgehog signaling; biallelic mutations cause SLSN7.
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "SDCCAG8 | SHH signaling and ciliogenesis regulator SDCCAG8 | hgnc:10671 | Disease-causing germline mutation(s) in"
explanation: >-
Orphanet lists SDCCAG8 as a disease-causing gene of Senior-Loken syndrome.
- name: WDR19
association: Causative
relationship_type: CAUSATIVE
subtype: SLSN8
gene_term:
preferred_term: WDR19
term:
id: hgnc:18340
label: WDR19
notes: >-
WDR19 encodes an intraflagellar transport-A (IFT-A) complex subunit; mutations
cause SLSN8 within a broader WDR19 ciliopathy spectrum.
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "WDR19 | WD repeat domain 19 | hgnc:18340 | Disease-causing germline mutation(s) in"
explanation: >-
Orphanet lists WDR19 as a disease-causing gene of Senior-Loken syndrome.
- name: NPHP3
association: Causative
relationship_type: CAUSATIVE
subtype: SLSN3
gene_term:
preferred_term: NPHP3
term:
id: hgnc:7907
label: NPHP3
notes: >-
NPHP3 (nephrocystin-3) is a component of the nephronophthisis protein network
at the ciliary transition zone. Family linkage to the NPHP3 locus in
Senior-Loken syndrome is the basis of the SLSN3 designation; MONDO:0011755
itself records no causal gene.
evidence:
- reference: PMID:22819833
reference_title: "Senior-Løken syndrome: a syndromic form of retinal dystrophy associated with nephronophthisis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Linkage to the NPHP3 locus has been shown in families with Senior-Løken syndrome (Omran et al., 2002)."
explanation: >-
Links the NPHP3 locus to the renal-retinal Senior-Loken phenotype through
family linkage, supporting NPHP3 as a cause of SLSN3.
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "NPHP3 | nephrocystin 3 | hgnc:7907 | Disease-causing germline mutation(s) in"
explanation: >-
Orphanet lists NPHP3 as a disease-causing gene of Senior-Loken syndrome.
- name: NPHP4
association: Causative
relationship_type: CAUSATIVE
subtype: SLSN4
gene_term:
preferred_term: NPHP4
term:
id: hgnc:19104
label: NPHP4
notes: >-
NPHP4 (nephrocystin-4/nephroretinin) mutations cause SLSN4; NPHP4 forms a
complex with NPHP1 at the ciliary transition zone.
case_fractions:
- population: >-
Chinese Senior-Loken syndrome case series, 74 molecularly solved patients
from 70 unrelated families
case_fraction_percent: 2.9
cohort_size: 70
notes: >-
NPHP4 was the joint fourth most frequent of the five genes solved in this
series, well behind CEP290 and IQCB1. The reported percentages are per
unrelated family, not per patient: at a denominator of 70 families the five
shares resolve to 43, 20, 3, 2 and 2 families and sum to exactly 70, which
74 does not reproduce for any of them.
evidence:
- reference: PMID:36990420
reference_title: "Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Variants in 5 genes were identified in 74 patients from 70 unrelated
families, including CEP290 (61.4%), IQCB1 (28.6%), NPHP1 (4.2%), NPHP4
(2.9%), and WDR19 (2.9%).
explanation: >-
Reports the NPHP4 share of molecularly solved Senior-Loken syndrome in
this cohort.
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "NPHP4 | nephrocystin 4 | hgnc:19104 | Disease-causing germline mutation(s) in"
explanation: >-
Orphanet lists NPHP4 as a disease-causing gene of Senior-Loken syndrome.
- name: INVS
association: Causative
relationship_type: CAUSATIVE
gene_term:
preferred_term: INVS
term:
id: hgnc:17870
label: INVS
notes: >-
INVS (inversin) mutations cause nephronophthisis type 2 / SLSN; inversin
shuttles between the cilium and cell junctions to coordinate developmental
pathways. INVS carries no numbered Senior-Loken class of its own in MONDO -
the nine children of MONDO:0017842 are SLSN1, SLSN3-SLSN9 and
nephronophthisis 15 - so it stays an umbrella-level causal gene here; the
INVS class MONDO:0011190 nephronophthisis 2 is bound on the Infantile
Nephronophthisis row of kb/disorders/Nephronophthisis.yaml.
evidence:
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "INVS | inversin | hgnc:17870 | Disease-causing germline mutation(s) in"
explanation: >-
Orphanet lists INVS as a disease-causing gene of Senior-Loken syndrome.
- name: CEP164
association: Causative
relationship_type: CAUSATIVE
gene_term:
preferred_term: CEP164
term:
id: hgnc:29182
label: CEP164
notes: >-
CEP164 is a distal appendage protein that anchors transition-zone components
and is required for ciliogenesis. The disease MONDO records for CEP164 is
nephronophthisis 15 (MONDO:0013917), which MONDO files as a child of both
nephronophthisis and Senior-Loken syndrome; a CEP164 patient with
nephronophthisis and retinitis pigmentosa is diagnosed as Senior-Loken
syndrome. That class is bound on the CEP164-related row of
kb/disorders/Nephronophthisis.yaml, so no subtype row is created here and
CEP164 stays an umbrella-level causal gene of this entry. Searching MONDO for
"SLSN10" (runoak -i ols:mondo search "SLSN10") and Europe PMC for "Senior-Loken
syndrome 10" and "SLSN10" returns no such concept.
evidence:
- reference: PMID:37324592
reference_title: "A novel pathogenic variant of CEP164 in an infant with Senior-Loken syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutations in the CEP164 gene can lead to a rare autosomal recessive
disorder known as Nephronophthisis 15 (NPHP15), which is characterized by
the early onset of kidney failure in children.
explanation: >-
Names nephronophthisis 15 as the CEP164 disease entity, in a case report
whose own CEP164 proband was diagnosed with Senior-Loken syndrome once
retinitis pigmentosa was established.
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "CEP164 | centrosomal protein 164 | hgnc:29182 | Disease-causing germline mutation(s) in"
explanation: >-
Orphanet lists CEP164 as a disease-causing gene of Senior-Loken syndrome.
- name: TRAF3IP1
association: Causative
relationship_type: CAUSATIVE
subtype: SLSN9
gene_term:
preferred_term: TRAF3IP1
term:
id: hgnc:17861
label: TRAF3IP1
notes: >-
TRAF3IP1 encodes IFT54, an intraflagellar transport B complex protein;
hypomorphic mutations cause SLSN9 within a spectrum of ciliopathies. HGNC
renamed this gene from TRAF3IP1 to IFT54 on 2026-03-20 (read from
rest.genenames.org), keeping the identifier hgnc:17861; the label is held at
the previous symbol because that is what the OBO build term validation reads
still carries.
evidence:
- reference: PMID:26487268
reference_title: "Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor
Interacting Protein 1) in eight patients from five families with
nephronophthisis (NPH) and retinal degeneration, two of the most common
manifestations of ciliopathies.
explanation: >-
Original report attributing the nephronophthisis-plus-retinal-degeneration
combination to TRAF3IP1 variants.
- reference: ORPHA:3156
reference_title: "Senior-Loken syndrome"
supports: SUPPORT
snippet: "TRAF3IP1 | TRAF3 interacting protein 1 | hgnc:17861 | Disease-causing germline mutation(s) (loss of function) in"
explanation: >-
Orphanet lists TRAF3IP1 as a disease-causing gene of Senior-Loken syndrome.
diagnosis:
- name: Clinical and Molecular Diagnosis
description: >-
Senior-Loken syndrome is suspected when nephronophthisis (chronic kidney
disease with corticomedullary cysts) co-occurs with a retinitis
pigmentosa-like retinal dystrophy, and is confirmed by identification of
biallelic pathogenic variants in one of the SLSN ciliary genes. Because of
marked genetic and phenotypic overlap with other ciliopathies, molecular
genetic testing (gene panel or exome) is central to establishing a definitive
diagnosis.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C19770
label: Molecular Analysis
evidence:
- reference: PMID:40427560
reference_title: "Senior-Loken Syndrome: Ocular Perspectives on Genetics, Pathogenesis, and Management."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Due to the genetic heterogeneity and significant phenotypic overlap with
other ciliopathies, establishing a definitive diagnosis during the initial
consultation remains a challenge for clinicians.
explanation: >-
Establishes that genetic heterogeneity and phenotypic overlap drive the
need for molecular diagnosis in Senior-Loken syndrome. (Source is a narrative review; classified as OTHER.)
differential_diagnoses:
- name: Isolated Nephronophthisis
description: >-
Isolated (non-syndromic) nephronophthisis shares the renal phenotype and
causative genes but lacks the retinal dystrophy that defines Senior-Loken
syndrome; retinal involvement occurs in roughly 10% of nephronophthisis
patients, constituting SLSN.
evidence:
- reference: PMID:15723066
reference_title: "Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ten percent of affected individuals have retinitis pigmentosa, constituting
the renal-retinal Senior-Loken syndrome (SLSN).
explanation: >-
Distinguishes Senior-Loken syndrome from isolated nephronophthisis by the
presence of retinitis pigmentosa.
- name: Leber Congenital Amaurosis
description: >-
CEP290-related Leber congenital amaurosis shares a causative gene with
CEP290-related Senior-Loken syndrome but presents as an isolated early-onset
retinal dystrophy without nephronophthisis; CEP290 is one of the most frequent
causes of LCA.
evidence:
- reference: PMID:16909394
reference_title: "Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CEP290 mutations therefore represent one of the most frequent causes of LCA
identified so far
explanation: >-
Documents CEP290 as a frequent cause of Leber congenital amaurosis, the
retinal-only differential of CEP290-related Senior-Loken syndrome.
treatments:
- name: Renal Replacement Therapy
description: >-
Because nephronophthisis progresses to end-stage renal disease, management
centers on renal replacement therapy — dialysis and kidney transplantation —
once stage 5 chronic kidney disease is reached. There is no disease-modifying
therapy that halts the underlying ciliopathy.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: kidney transplantation
term:
id: NCIT:C15289
label: Organ Transplantation
- name: Low-Vision Supportive Care
description: >-
Ophthalmologic management is supportive, comprising low-vision rehabilitation
and visual aids for the progressive retinal dystrophy; no proven therapy
reverses the photoreceptor degeneration.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
- name: Genetic Counseling
description: >-
Autosomal recessive inheritance entails a 25% sibling recurrence risk. Once
the biallelic variants are identified, carrier testing, prenatal testing, and
preimplantation genetic testing become available to families.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
review_notes: >-
Senior-Loken syndrome is a lumped renal-retinal ciliopathy entry created to
cover the SLSN1-9 gene-level MONDO leaf classes (per GitHub issue 4243) under the
umbrella term MONDO:0017842. Subtypes are represented as gene-level
has_subtypes rather than separate thin files, following the repository
convention for gene-numbered MONDO splits. The mechanism is anchored to the
ciliopathy_dysfunction module: transition-zone dysfunction (shared lesion)
bifurcating into the renal (nephronophthisis) and retinal (photoreceptor
connecting-cilium) arms. Initial evidence backbone is the Orphanet structured
record (ORPHA:3156) plus verified primary/review literature; additional
pathophysiology depth is a follow-up opportunity.
MONDO:0017842 has nine children: SLSN1, SLSN3 through SLSN9, and
nephronophthisis 15. Eight of the nine are bound on has_subtypes rows here.
The ninth, MONDO:0013917 nephronophthisis 15 (CEP164), is bound on the
CEP164-related row of kb/disorders/Nephronophthisis.yaml, which MONDO also
files it under; CEP164 is kept here as an umbrella-level causal gene instead of
being given a second home. Synonym-inclusive MONDO searches for "SLSN2" and
"Senior-Loken syndrome 2" return nothing, so the series skips 2; the
corresponding INVS concept is MONDO:0011190 nephronophthisis 2, which likewise
sits in that entry.
ClinGen cannot grade these subtypes: its committed Gene-Disease Validity
download asserts NPHP4 against nephronophthisis 4, NPHP3 against
nephronophthisis, CEP164 against CEP164-related ciliopathy and TRAF3IP1 against
ciliopathy, and none against a Senior-Loken class, so those Definitive grades
are not transferable here.
classifications:
harrisons_chapter:
- classification_value: KIDNEY_URINARY_TRACT
- classification_value: GENETICS_ENVIRONMENT_DISEASE
mechanistic_category:
- classification_value: ciliopathy
references:
- reference: PMID:15723066
title: "Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin."
- reference: PMID:16885411
title: "Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia."
- reference: PMID:16909394
title: "Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis."
- reference: PMID:21071979
title: "Mechanisms of nephronophthisis and related ciliopathies."
- reference: PMID:12438707
title: "Candidate gene analysis of KIAA0678 encoding a DnaJ-like protein for adolescent nephronophthisis and Senior-Løken syndrome type 3."
- reference: PMID:22819833
title: "Senior-Løken syndrome: a syndromic form of retinal dystrophy associated with nephronophthisis."
- reference: PMID:26487268
title: "Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization."
- reference: PMID:36990420
title: "Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4."
- reference: PMID:37324592
title: "A novel pathogenic variant of CEP164 in an infant with Senior-Loken syndrome."
- reference: PMID:40427560
title: "Senior-Loken Syndrome: Ocular Perspectives on Genetics, Pathogenesis, and Management."
- reference: ORPHA:3156
title: "Senior-Loken syndrome"